lovingscience/chembl-v37-raw-activities huggingface dataset:
Compound (SMILES): COCC(C)c1nc2cc(-c3noc(=O)[nH]3)nc(-c3cncc(Cl)c3)c2n1C(C)[C@H]1CC[C@H](C)CC1
InChIKey: BOHJWRUCGNOBMS-GQRAJKLCSA-N
Target: E3 ubiquitin-protein ligase Mdm2 (SINGLE PROTEIN), Homo sapiens
UniProt: Q00987
Assay: FRET Assay: Methods: An HDM2 FRET assay was developed to assess the compounds' inhibitory activity towards binding of p53 protein. A truncated version of HDM2 with residues 17 to 125 (containing p53 binding surface, Science (1994) 265, 346-355), with N-terminal His and Thioredoxin tag was generated in pET32a expression vector and expressed in E. coli strain BL21(DE3)Rosetta. Protein was purified using Ni-affinity chromatography, followed by size exclusion chromatography using Superdex 75 26/60 column. To assess inhibition of p53 binding to HDM2, a FITC labeled 8-mer peptide (SEQ ID NO:1: Ac-Phe-Arg-Dpr-Ac6c-(6-Br)Trp-Glu-Glu-Leu-NH2; Anal Biochem. 2004 Aug. 1; 331(1):138-46) with strong affinity towards the p53 binding pocket of HDM2 was used. The HDM2 assay buffer contained 1x Phosphate Buffered Saline (Invitrogen, Cat#14190), 0.01% BSA (Jackson ImmunoResearch, Cat#001-000-162), 0.01% Tween-20.
Measurement: IC50 = 161 nM (pChEMBL 6.789999961853027)
Descriptors: MW 511.03, ALogP 5.63, HBA 8, HBD 1, PSA 111.72, QED 0.34
Compound (SMILES): CCOC(c1nc2cc(-c3noc(=O)[nH]3)nc(-c3cncc(Cl)c3)c2n1C(C)[C@H]1CC[C@H](C)CC1)C1CC1
InChIKey: PJGMHURMTNPVFZ-RNFMHXQYSA-N
Target: E3 ubiquitin-protein ligase Mdm2 (SINGLE PROTEIN), Homo sapiens
UniProt: Q00987
Assay: FRET Assay: Methods: An HDM2 FRET assay was developed to assess the compounds' inhibitory activity towards binding of p53 protein. A truncated version of HDM2 with residues 17 to 125 (containing p53 binding surface, Science (1994) 265, 346-355), with N-terminal His and Thioredoxin tag was generated in pET32a expression vector and expressed in E. coli strain BL21(DE3)Rosetta. Protein was purified using Ni-affinity chromatography, followed by size exclusion chromatography using Superdex 75 26/60 column. To assess inhibition of p53 binding to HDM2, a FITC labeled 8-mer peptide (SEQ ID NO:1: Ac-Phe-Arg-Dpr-Ac6c-(6-Br)Trp-Glu-Glu-Leu-NH2; Anal Biochem. 2004 Aug. 1; 331(1):138-46) with strong affinity towards the p53 binding pocket of HDM2 was used. The HDM2 assay buffer contained 1x Phosphate Buffered Saline (Invitrogen, Cat#14190), 0.01% BSA (Jackson ImmunoResearch, Cat#001-000-162), 0.01% Tween-20. In the 1x assay buffer recombinant HDM2 protein, peptide and Lumi-4-Tb Cryptate-conjugate mouse.
Measurement: IC50 < 1 nM (pChEMBL 9)
Descriptors: MW 537.06, ALogP 6.36, HBA 8, HBD 1, PSA 111.72, QED 0.28
Compound (SMILES): COc1cc(Nc2ncc(Br)c(N[C@H](C)[C@H](C)O)n2)ccc1S(C)(=N)=O
InChIKey: GNODSQUZRSUVER-QILFFNKJSA-N
Target: Cyclin-dependent kinase 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P24941
Assay: Kinase Assay: Kinase assay using either CDK1, CDK2 or VEGFR-2.
Measurement: IC50 = 3 nM (pChEMBL 8.520000457763672)
Descriptors: MW 444.36, ALogP 3.21, HBA 8, HBD 4, PSA 120.22, QED 0.52
Compound (SMILES): COc1cc(Nc2ncc(Br)c(N[C@H](C)C(C)(C)O)n2)ccc1S(C)(=N)=O
InChIKey: VEMUNZLIOXAWMA-VQLJPOJZSA-N
Target: Vascular endothelial growth factor receptor 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P35968
Assay: Kinase Assay: Kinase assay using either CDK1, CDK2 or VEGFR-2.
Measurement: IC50 = 75 nM (pChEMBL 7.119999885559082)
Descriptors: MW 458.38, ALogP 3.6, HBA 8, HBD 4, PSA 120.22, QED 0.5
Compound (SMILES): CCS(=N)(=O)c1ccc(Nc2ncc(Br)c(N[C@H](C)C(C)(C)O)n2)cc1
InChIKey: BIOJVWLNPPOUGW-RRSIMWOXSA-N
Target: Cyclin-dependent kinase 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P24941
Assay: Kinase Assay: Kinase assay using either CDK1, CDK2 or VEGFR-2.
Measurement: IC50 = 27 nM (pChEMBL 7.570000171661377)
Descriptors: MW 442.38, ALogP 3.98, HBA 7, HBD 4, PSA 110.99, QED 0.52
Compound (SMILES): Cc1cc(Nc2ncc(Br)c(N[C@H](C)C(C)(C)O)n2)ccc1S(C)(=N)=O
InChIKey: GKJRCQIJVHMRJB-RRSIMWOXSA-N
Target: Cyclin-dependent kinase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P06493
Assay: Kinase Assay: Kinase assay using either CDK1, CDK2 or VEGFR-2.
Measurement: IC50 = 4 nM (pChEMBL 8.399999618530273)
Descriptors: MW 442.38, ALogP 3.9, HBA 7, HBD 4, PSA 110.99, QED 0.54
Compound (SMILES): CNc1nc2ccccc2n1-c1nc(N2CCOC[C@H]2C)cc(C2([S@](C)(=N)=O)CC2)n1
InChIKey: JESNSKPPMWEWAT-JKGBWWFKSA-N
Target: Serine/threonine-protein kinase ATR (SINGLE PROTEIN), Homo sapiens
UniProt: Q13535
Assay: Inhibition of ATR in human HT29 cells after 60 mins by Hoechst 33258 staining-based assay
Measurement: IC50 = 9 nM (pChEMBL 8.050000190734863)
Descriptors: MW 441.56, ALogP 2.75, HBA 9, HBD 2, PSA 109.02, QED 0.63
Compound (SMILES): CC(=O)NCC[C@@H]1CCc2ccc3nc(C)oc3c21
InChIKey: CCRUCMHMQXUZAT-LBPRGKRZSA-N
Target: Melatonin receptor type 1A (SINGLE PROTEIN), Homo sapiens
UniProt: P48039
Assay: Agonist activity at human MT1 expressed in CHO-K1 cells assessed as inhibition of forskolin-induced cAMP accumulation incubated for 30 mins by AlphaScreen assay
Measurement: EC50 = 0.015 nM (pChEMBL 10.819999694824219)
Descriptors: MW 258.32, ALogP 2.69, HBA 3, HBD 1, PSA 55.13, QED 0.92
Compound (SMILES): O=C(N[C@@H](CC1CCCCC1)C(=O)N1CC[C@H]2OCC(=O)[C@H]21)c1ccccc1
InChIKey: ZDRBMNHVJWTCNG-DFQSSKMNSA-N
Target: Procathepsin L (SINGLE PROTEIN), Homo sapiens
UniProt: P07711
Assay: In Vitro Inhibition Assay: In vitro inhibition assay using cathepsin.
Measurement: Ki = 1700 nM (pChEMBL 5.769999980926514)
Descriptors: MW 384.48, ALogP 2.32, HBA 4, HBD 1, PSA 75.71, QED 0.85
Compound (SMILES): O=C(N[C@H](C(=O)N1CC[C@H]2OCC(=O)[C@H]21)C1CCCCC1)c1ccccc1
InChIKey: JHKBBDALNAZURK-CEXWTWQISA-N
Target: Cathepsin K (SINGLE PROTEIN), Homo sapiens
UniProt: P43235
Assay: In Vitro Inhibition Assay: In vitro inhibition assay using cathepsin.
Measurement: Ki = 305 nM (pChEMBL 6.519999980926514)
Descriptors: MW 370.45, ALogP 1.93, HBA 4, HBD 1, PSA 75.71, QED 0.88
Compound (SMILES): O=C(N[C@H](C(=O)N1C[C@H](F)[C@H]2OCC(=O)[C@H]21)C1CCCCC1)c1ccccc1
InChIKey: KKKHMKQUVHHTJX-GDAAHCPNSA-N
Target: Procathepsin L (SINGLE PROTEIN), Homo sapiens
UniProt: P07711
Assay: In Vitro Inhibition Assay: In vitro inhibition assay using cathepsin.
Measurement: Ki = 580 nM (pChEMBL 6.239999771118164)
Descriptors: MW 388.44, ALogP 1.88, HBA 4, HBD 1, PSA 75.71, QED 0.85
Compound (SMILES): O=C(N[C@H](C(=O)N1C[C@H](Cl)[C@H]2OCC(=O)[C@H]21)C1CCCCC1)c1ccccc1
InChIKey: LBLSSIHBMJKAIZ-GDAAHCPNSA-N
Target: Cathepsin S (SINGLE PROTEIN), Homo sapiens
UniProt: P25774
Assay: In Vitro Inhibition Assay: In vitro inhibition assay using cathepsin.
Measurement: Ki = 8.5 nM (pChEMBL 8.069999694824219)
Descriptors: MW 404.89, ALogP 2.15, HBA 4, HBD 1, PSA 75.71, QED 0.78
Compound (SMILES): C[C@H]1CC[C@H]([C@H](NC(=O)c2ccccc2)C(=O)N2C[C@H](F)[C@H]3OCC(=O)[C@H]32)CC1
InChIKey: KLJDDHMAENWYIR-DZJPNTAKSA-N
Target: Cathepsin K (SINGLE PROTEIN), Homo sapiens
UniProt: P43235
Assay: In Vitro Inhibition Assay: In vitro inhibition assay using cathepsin.
Measurement: Ki > 10000 nM (pChEMBL 5)
Descriptors: MW 402.47, ALogP 2.13, HBA 4, HBD 1, PSA 75.71, QED 0.84
Compound (SMILES): C[C@H]1CC[C@H]([C@H](NC(=O)c2ccccc2)C(=O)N2C[C@H](Cl)[C@H]3OCC(=O)[C@H]32)CC1
InChIKey: ZFKPOKNTFMTPJB-DZJPNTAKSA-N
Target: Cathepsin L2 (SINGLE PROTEIN), Homo sapiens
UniProt: O60911
Assay: In Vitro Inhibition Assay: In vitro inhibition assay using cathepsin.
Measurement: Ki > 10000 nM (pChEMBL 5)
Descriptors: MW 418.92, ALogP 2.4, HBA 4, HBD 1, PSA 75.71, QED 0.76
Compound (SMILES): C[C@H]1CC[C@H]([C@H](NC(=O)c2ccccc2)C(=O)N2C[C@@H](Cl)[C@H]3OCC(=O)[C@H]32)CC1
InChIKey: ZFKPOKNTFMTPJB-VHYIGOAFSA-N
Target: Cathepsin S (SINGLE PROTEIN), Homo sapiens
UniProt: P25774
Assay: In Vitro Inhibition Assay: In vitro inhibition assay using cathepsin.
Measurement: Ki = 75 nM (pChEMBL 7.119999885559082)
Descriptors: MW 418.92, ALogP 2.4, HBA 4, HBD 1, PSA 75.71, QED 0.76
Compound (SMILES): O=C(N[C@H](C(=O)N1CC[C@H]2OCC(=O)[C@H]21)C1CCCCC1)c1cccc(-n2cnnn2)c1
InChIKey: VHBCENDEKXXWEY-HSALFYBXSA-N
Target: Cathepsin B (SINGLE PROTEIN), Homo sapiens
UniProt: P07858
Assay: In Vitro Inhibition Assay: In vitro inhibition assay using cathepsin.
Measurement: Ki > 10000 nM (pChEMBL 5)
Descriptors: MW 438.49, ALogP 0.91, HBA 8, HBD 1, PSA 119.31, QED 0.74
Compound (SMILES): O=C(N[C@H](C(=O)N1C[C@H](F)[C@H]2OCC(=O)[C@H]21)C1CCCCC1)c1cccc(-n2cnnn2)c1
InChIKey: KYTNNKTVWKSLGW-IJXRJRJASA-N
Target: Cathepsin S (SINGLE PROTEIN), Homo sapiens
UniProt: P25774
Assay: In Vitro Inhibition Assay: In vitro inhibition assay using cathepsin.
Measurement: Ki = 50 nM (pChEMBL 7.300000190734863)
Descriptors: MW 456.48, ALogP 0.86, HBA 8, HBD 1, PSA 119.31, QED 0.71
Compound (SMILES): O=C(N[C@H](C(=O)N1C[C@H](Cl)[C@H]2OCC(=O)[C@H]21)C1CCCCC1)c1cccc(-n2cnnn2)c1
InChIKey: OGRMAGULSQOTTD-IJXRJRJASA-N
Target: Cathepsin B (SINGLE PROTEIN), Homo sapiens
UniProt: P07858
Assay: In Vitro Inhibition Assay: In vitro inhibition assay using cathepsin.
Measurement: Ki = 650 nM (pChEMBL 6.190000057220459)
Descriptors: MW 472.93, ALogP 1.13, HBA 8, HBD 1, PSA 119.31, QED 0.65
Compound (SMILES): C[C@H]1CC[C@H]([C@H](NC(=O)c2cccc(-n3cnnn3)c2)C(=O)N2CC[C@H]3OCC(=O)[C@H]32)CC1
InChIKey: DRETYBQYKAFRPH-BHOULKKZSA-N
Target: Cathepsin L2 (SINGLE PROTEIN), Homo sapiens
UniProt: O60911
Assay: In Vitro Inhibition Assay: In vitro inhibition assay using cathepsin.
Measurement: Ki > 10000 nM (pChEMBL 5)
Descriptors: MW 452.52, ALogP 1.16, HBA 8, HBD 1, PSA 119.31, QED 0.72
Compound (SMILES): C[C@H]1CC[C@H]([C@H](NC(=O)c2cccc(-n3cnnn3)c2)C(=O)N2C[C@H](F)[C@H]3OCC(=O)[C@H]32)CC1
InChIKey: RHGFQOZUQWCCRF-UEWVETAJSA-N
Target: Procathepsin L (SINGLE PROTEIN), Homo sapiens
UniProt: P07711
Assay: In Vitro Inhibition Assay: In vitro inhibition assay using cathepsin.
Measurement: Ki > 10000 nM (pChEMBL 5)
Descriptors: MW 470.51, ALogP 1.1, HBA 8, HBD 1, PSA 119.31, QED 0.7
Compound (SMILES): C[C@H]1CC[C@H]([C@H](NC(=O)c2cccc(-n3cnnn3)c2)C(=O)N2C[C@H](Cl)[C@H]3OCC(=O)[C@H]32)CC1
InChIKey: BNTXXZPUXMSHRP-UEWVETAJSA-N
Target: Cathepsin L2 (SINGLE PROTEIN), Homo sapiens
UniProt: O60911
Assay: In Vitro Inhibition Assay: In vitro inhibition assay using cathepsin.
Measurement: Ki > 10000 nM (pChEMBL 5)
Descriptors: MW 486.96, ALogP 1.37, HBA 8, HBD 1, PSA 119.31, QED 0.63
Compound (SMILES): C[C@H]1CC[C@H]([C@H](NC(=O)c2cccc(-n3cnnn3)c2)C(=O)N2C[C@@H](Cl)[C@H]3OCC(=O)[C@H]32)CC1
InChIKey: BNTXXZPUXMSHRP-VWIQXFRCSA-N
Target: Cathepsin L2 (SINGLE PROTEIN), Homo sapiens
UniProt: O60911
Assay: In Vitro Inhibition Assay: In vitro inhibition assay using cathepsin.
Measurement: Ki > 10000 nM (pChEMBL 5)
Descriptors: MW 486.96, ALogP 1.37, HBA 8, HBD 1, PSA 119.31, QED 0.63
Compound (SMILES): CC1(C)CCC([C@H](NC(=O)c2cccc(-n3cnnn3)c2)C(=O)N2C[C@H](Cl)[C@H]3OCC(=O)[C@H]32)CC1
InChIKey: CCMWMJVCRVOQCI-MJUUVYJYSA-N
Target: Cathepsin S (SINGLE PROTEIN), Homo sapiens
UniProt: P25774
Assay: In Vitro Inhibition Assay: In vitro inhibition assay using cathepsin.
Measurement: Ki = 12 nM (pChEMBL 7.920000076293945)
Descriptors: MW 500.99, ALogP 1.76, HBA 8, HBD 1, PSA 119.31, QED 0.62
Compound (SMILES): O=C(N[C@H](C(=O)N1C[C@H](Cl)[C@H]2OCC(=O)[C@H]21)C1CCCCC1)c1cccc(-n2ccnc2)c1
InChIKey: JPQIXMPQVCDFBY-VXSCBNMQSA-N
Target: Cathepsin B (SINGLE PROTEIN), Homo sapiens
UniProt: P07858
Assay: In Vitro Inhibition Assay: In vitro inhibition assay using cathepsin.
Measurement: Ki = 440 nM (pChEMBL 6.360000133514404)
Descriptors: MW 470.96, ALogP 2.34, HBA 6, HBD 1, PSA 93.53, QED 0.68
Compound (SMILES): O=C(N[C@H](C(=O)N1C[C@@H](Cl)[C@H]2OCC(=O)[C@H]21)C1CCCCC1)c1cccc(-n2ccnc2)c1
InChIKey: JPQIXMPQVCDFBY-FVTFTPSCSA-N
Target: Procathepsin L (SINGLE PROTEIN), Homo sapiens
UniProt: P07711
Assay: In Vitro Inhibition Assay: In vitro inhibition assay using cathepsin.
Measurement: Ki = 1900 nM (pChEMBL 5.71999979019165)
Descriptors: MW 470.96, ALogP 2.34, HBA 6, HBD 1, PSA 93.53, QED 0.68
Compound (SMILES): C[C@H]1CC[C@H]([C@H](NC(=O)c2cccc(-n3ccnc3)c2)C(=O)N2C[C@H](F)[C@H]3OCC(=O)[C@H]32)CC1
InChIKey: GXCSFFZWKWHFDR-YKHRXLODSA-N
Target: Cathepsin K (SINGLE PROTEIN), Homo sapiens
UniProt: P43235
Assay: In Vitro Inhibition Assay: In vitro inhibition assay using cathepsin.
Measurement: Ki > 10000 nM (pChEMBL 5)
Descriptors: MW 468.53, ALogP 2.31, HBA 6, HBD 1, PSA 93.53, QED 0.73
Compound (SMILES): C[C@H]1CC[C@H]([C@H](NC(=O)c2cccc(-n3ccnc3)c2)C(=O)N2C[C@H](Cl)[C@H]3OCC(=O)[C@H]32)CC1
InChIKey: AWBHNFADBGSDNV-YKHRXLODSA-N
Target: Cathepsin S (SINGLE PROTEIN), Homo sapiens
UniProt: P25774
Assay: In Vitro Inhibition Assay: In vitro inhibition assay using cathepsin.
Measurement: Ki = 0.4 nM (pChEMBL 9.399999618530273)
Descriptors: MW 484.98, ALogP 2.58, HBA 6, HBD 1, PSA 93.53, QED 0.66
Compound (SMILES): O=C(NC(CC1CCCCC1)C(=O)N1CC[C@H]2OCC(=O)[C@H]21)c1ccccc1
InChIKey: ZDRBMNHVJWTCNG-IPNZSQQUSA-N
Target: Cathepsin S (SINGLE PROTEIN), Homo sapiens
UniProt: P25774
Assay: In Vitro Inhibition Assay: In vitro inhibition assay using cathepsin.
Measurement: Ki = 555 nM (pChEMBL 6.260000228881836)
Descriptors: MW 384.48, ALogP 2.32, HBA 4, HBD 1, PSA 75.71, QED 0.85
Compound (SMILES): Cc1nc(-c2c(F)cc(Cl)cc2-c2cnc3c(c2)CCC3NC(=O)C2(NC(=O)c3ccnnc3)CC2)no1
InChIKey: VKQZQIDNZZTHCQ-UHFFFAOYSA-N
Target: B1 bradykinin receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P46663
Assay: Calcium Mobilization Assay: Calcium mobilization assay using Bradykinin-1 receptor.
Measurement: IC50 = 35.2 nM (pChEMBL 7.449999809265137)
Descriptors: MW 533.95, ALogP 3.76, HBA 8, HBD 2, PSA 135.79, QED 0.38
Compound (SMILES): Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCCC(N)C(F)C1
InChIKey: XFQXLZJUIKQXOU-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase pim-2 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9P1W9
Assay: Inhibition of recombinant human PIM2 using FAM-pimtide as substrate after 90 mins by Z-LYTE assay
Measurement: Ki = 0.4 nM (pChEMBL 9.399999618530273)
Descriptors: MW 465.51, ALogP 2.92, HBA 8, HBD 3, PSA 115.09, QED 0.55
Compound (SMILES): Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CC[C@@H](N)[C@H](F)CC1
InChIKey: NHXVGMQFCYBLTL-ZWNOBZJWSA-N
Target: Cytochrome P450 3A4 (SINGLE PROTEIN), Homo sapiens
UniProt: P08684
Assay: Reversible inhibition of CYP3A4 (unknown origin) using testosterone as substrate
Measurement: IC50 = 6300 nM (pChEMBL 5.199999809265137)
Descriptors: MW 465.51, ALogP 2.92, HBA 8, HBD 3, PSA 115.09, QED 0.55
Compound (SMILES): Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1C1CCC(N)CC(C)(O)C1
InChIKey: CATWESQSWJEUNP-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase pim-1 (SINGLE PROTEIN), Homo sapiens
UniProt: P11309
Assay: Pim Kinase Binding Activity: PIM-1, -2, and -3 enzymes were generated as fusion proteins expressed in bacteria and purified by IMAC column chromatography (Sun, X., Chiu, J. F., and He, Q. Y. (2005) Expert Rev. Proteomics, 2:649-657). A fluorescent-labeled Pim-specific peptide substrate, was custom synthesized by American Peptide Company (Sunnyvale, Calif.). A fluorescent-labeled Pim-specific peptide substrate, was custom synthesized by American Peptide Company (Sunnyvale, Calif.). Reaction Buffer contained 10 mM HEPES, pH 7.2, 10 mM MgCl2, 0.01% Tween 20, 2 mM DTT. Termination Buffer contained 190 mM HEPES, pH 7.2, 0.015% Brij-35, 0.2% Coating Reagent 3 (Caliper Life Sciences, Hopkinton, Mass.), 20 mM EDTA. Separation Buffer contained 100 mM HEPES, pH 7.2, 0.015% Brij-35, 0.1% Coating Reagent 3, 1:200 Coating Reagent 8 (Caliper Life Sciences, Hopkinton, Mass.), 10 mM EDTA and 5% DMSO.
Measurement: Ki = 0.139 nM (pChEMBL 9.859999656677246)
Descriptors: MW 476.55, ALogP 3.39, HBA 8, HBD 4, PSA 132.08, QED 0.43
Compound (SMILES): Cc1cc(COc2ccc(S(=O)(=O)NC[C@@H](C(=O)NO)N3CCN(S(C)(=O)=O)CC3)cc2)c2ccccc2n1
InChIKey: IVLLKNCAVYHIFI-DEOSSOPVSA-N
Target: Matrix metalloproteinase-9 (SINGLE PROTEIN), Homo sapiens
UniProt: P14780
Assay: Inhibition Assay: The molecules are dose-response tested on the following enzymes: MMP1, MMP3, MMP9, ADAM9 and ADAM10, according to the same protocol as that described for the TACE enzyme in example 28, but with different substrates (MMP R&D systems, reference: P126-990, and ADAM R&D systems, reference: ES003).
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 577.69, ALogP 0.85, HBA 9, HBD 3, PSA 158.24, QED 0.23
Compound (SMILES): Cc1cc(COc2ccc(S(=O)(=O)NC[C@@H](C(=O)NO)N3CCN(Cc4ccc(F)cc4)CC3)cc2)c2ccccc2n1
InChIKey: UWCNFKCKFSEPKW-PMERELPUSA-N
Target: Disintegrin and metalloproteinase domain-containing protein 10 (SINGLE PROTEIN), Homo sapiens
UniProt: O14672
Assay: Inhibition Assay: The molecules are dose-response tested on the following enzymes: MMP1, MMP3, MMP9, ADAM9 and ADAM10, according to the same protocol as that described for the TACE enzyme in example 28, but with different substrates (MMP R&D systems, reference: P126-990, and ADAM R&D systems, reference: ES003).
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 607.71, ALogP 3.23, HBA 8, HBD 3, PSA 124.1, QED 0.18
Compound (SMILES): CCN1CCN([C@@H](CNS(=O)(=O)c2ccc(OCc3cc(C)nc4ccccc34)cc2)C(=O)NO)CC1
InChIKey: UFNKXVJYCDHZQW-VWLOTQADSA-N
Target: Disintegrin and metalloproteinase domain-containing protein 9 (SINGLE PROTEIN), Homo sapiens
UniProt: Q13443
Assay: Inhibition Assay: The molecules are dose-response tested on the following enzymes: MMP1, MMP3, MMP9, ADAM9 and ADAM10, according to the same protocol as that described for the TACE enzyme in example 28, but with different substrates (MMP R&D systems, reference: P126-990, and ADAM R&D systems, reference: ES003).
Measurement: IC50 = 3054 nM (pChEMBL 5.510000228881836)
Descriptors: MW 527.65, ALogP 1.91, HBA 8, HBD 3, PSA 124.1, QED 0.27
Compound (SMILES): Cc1ccc(CN2CCN([C@@H](CNS(=O)(=O)c3ccc(OCc4cc(C)nc5ccccc45)cc3)C(=O)NO)CC2)cc1
InChIKey: OEKBBQNVZPGHFU-HKBQPEDESA-N
Target: Disintegrin and metalloproteinase domain-containing protein 9 (SINGLE PROTEIN), Homo sapiens
UniProt: Q13443
Assay: Inhibition Assay: The molecules are dose-response tested on the following enzymes: MMP1, MMP3, MMP9, ADAM9 and ADAM10, according to the same protocol as that described for the TACE enzyme in example 28, but with different substrates (MMP R&D systems, reference: P126-990, and ADAM R&D systems, reference: ES003).
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 603.75, ALogP 3.4, HBA 8, HBD 3, PSA 124.1, QED 0.18
Compound (SMILES): Cc1cc(COc2ccc(S(=O)(=O)NC[C@@H](C(=O)NO)N3CCN(C(=O)C(C)C)CC3)cc2)c2ccccc2n1
InChIKey: NVPQXUAYORUQIU-SANMLTNESA-N
Target: Disintegrin and metalloproteinase domain-containing protein 9 (SINGLE PROTEIN), Homo sapiens
UniProt: Q13443
Assay: Inhibition Assay: The molecules are dose-response tested on the following enzymes: MMP1, MMP3, MMP9, ADAM9 and ADAM10, according to the same protocol as that described for the TACE enzyme in example 28, but with different substrates (MMP R&D systems, reference: P126-990, and ADAM R&D systems, reference: ES003).
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 569.68, ALogP 2.07, HBA 8, HBD 3, PSA 141.17, QED 0.25
Compound (SMILES): Cc1cc(COc2ccc(S(=O)(=O)NC[C@@H](C(=O)NO)N3CCN(S(=O)(=O)CC(C)C)CC3)cc2)c2ccccc2n1
InChIKey: IUVIWMVVODOSQU-MHZLTWQESA-N
Target: Disintegrin and metalloproteinase domain-containing protein 9 (SINGLE PROTEIN), Homo sapiens
UniProt: Q13443
Assay: Inhibition Assay: The molecules are dose-response tested on the following enzymes: MMP1, MMP3, MMP9, ADAM9 and ADAM10, according to the same protocol as that described for the TACE enzyme in example 28, but with different substrates (MMP R&D systems, reference: P126-990, and ADAM R&D systems, reference: ES003).
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 619.77, ALogP 1.88, HBA 9, HBD 3, PSA 158.24, QED 0.2
Compound (SMILES): Cc1cc(COc2ccc(S(=O)(=O)NC[C@@H](C(=O)NO)N3CCN(S(=O)(=O)C(C)C)CC3)cc2)c2ccccc2n1
InChIKey: AHKGXKHDKHAJDE-SANMLTNESA-N
Target: Disintegrin and metalloproteinase domain-containing protein 9 (SINGLE PROTEIN), Homo sapiens
UniProt: Q13443
Assay: Inhibition Assay: The molecules are dose-response tested on the following enzymes: MMP1, MMP3, MMP9, ADAM9 and ADAM10, according to the same protocol as that described for the TACE enzyme in example 28, but with different substrates (MMP R&D systems, reference: P126-990, and ADAM R&D systems, reference: ES003).
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 605.74, ALogP 1.63, HBA 9, HBD 3, PSA 158.24, QED 0.22
Compound (SMILES): Cc1cc(C)nc(N2CC3CN(C(=O)c4ccccc4-n4nccn4)CC3C2)n1
InChIKey: LCDKKZMNYHMDCH-UHFFFAOYSA-N
Target: Orexin/Hypocretin receptor type 1 (SINGLE PROTEIN), Homo sapiens
UniProt: O43613
Assay: Human Orexin 1 Receptor Radioligand Binding Studies: Chinese ovary cells (CHO) stably expressing human orexin 1 receptor (Genebank accession number NM_001526) were grown to confluency in DMEM/F12 (Gibco, Cat #11039), 10% FBS, 1× Pen/Strep, 600 μg/mL G418 media on 150 cm2 tissue culture plates, washed with 5 mM EDTA in PBS (HyClone Dulbecco's Phosphate Buffered Saline 1× with Calcium and Magnesium, Cat #SH30264.01, hereafter referred to simply as PBS) and scraped into 50 ml tubes. After centrifugation (2K xG, 10 min at 4° C.), the supernatant was aspirated and the pellets frozen and stored at −80° C. Cells were resuspended in PBS in the presence of 1 tablet of protease inhibitor cocktail (Roche, Cat. #11836145001) per 50 mL. Each cell pellet from a 15 cm plate was resuspended in 10 mL, stored on ice, and vortexed for 45 sec prior to addition to the reactions. Competition binding experiments in 96 well polypropylene plates were performed using [3H]-SB674042 (Moravek Corporation, specific activity=35.3 Ci/mmol), diluted to a 10 nM concentration in PBS (4 nM final). Compounds were solubilized in 100% DMSO (Acros Organics, Cat. #61042-1000) and tested over a range of 7 concentrations (from 0.1 nM to 10 μM). The final concentration of DMSO in the reactions is equal to or less than 0.1%. Total and nonspecific binding was determined in the absence and presence of 10 μM (1-(6,8-difluoro-2-methylquinolin-4-yl)-3-[4-(dimethylamino)phenyl]urea, CAS Registry #288150-92-5). The total volume of each reaction is 200 μL (20 μL of diluted compounds, 80 μL of [3H]-SB674042 diluted in PBS and 100 μL of the cell suspension). Reactions were run for 60 min at room temperature and terminated by filtration through GF/C filter plates (PerkinElmer, Cat. #6005174) presoaked in 0.3% polyethylenimine using the cell harvester (PerkinElmer Filtermate). The plates were washed 3 times by aspirating 30 ml PBS through the plates. Plates were dried in 55° C. oven for 60 min, scintillation fluid was added, and the radioactivity was counted on a Topcount (Packard).IC50 values (i.e. concentration of unlabelled compound required to compete for 50% of specific binding to the radioligand) were calculated using the GraphPad Prism software (GraphPad Prism Software Inc., San Diego, Calif.) with a fit to a sigmoidal dose-response curve. Apparent Ki values were calculated as Ki=IC50/(1+C/Kd), where C is concentration of radioligand and Kd=4 nM.
Measurement: Ki = 10000 nM (pChEMBL 5)
Descriptors: MW 389.46, ALogP 1.88, HBA 7, HBD 0, PSA 80.04, QED 0.68
Compound (SMILES): Cc1cc(N2CC3CN(C(=O)c4cc(F)ccc4-n4nccn4)CC3C2)nc(C)n1
InChIKey: CSEMOFQEGNLVDE-UHFFFAOYSA-N
Target: Orexin receptor type 2 (SINGLE PROTEIN), Homo sapiens
UniProt: O43614
Assay: Receptor Radioligand Binding Assay: HEK293 stably expressing human orexin-2 receptor (Genebank accession number NM_001526) were grown to confluency in DMEM/F12 (Gibco, Cat #11039), in DMEM, 10% FBS, 1× Pen/Strep, 1× NaPyruvate, 1×HEPES, 600 ug/ml G418 media on 150 cm2 tissue culture plates, washed with 5 mM EDTA in PBS (HyClone Dulbecco's Phosphate Buffered Saline 1× with Calcium and Magnesium, Cat # SH30264.01, hereafter referred to simply as PBS) and scraped into 50 ml tubes. After centrifugation (2K×G, 10 min at 4° C.), the supernatant was aspirated and the pellets frozen and stored at −80° C. Cells were resuspended in PBS in the presence of 1 tablet of protease inhibitor cocktail (Roche, Cat. #11836145001) per 50 mL. Each cell pellet from a 15 cm plate was resuspended in 10 mL, stored on ice, and vortexed for 45 sec just prior to addition to the reactions. Competition binding experiments in 96 well polypropylene plates were performed using [3H]-EMPA (Moravek Corporation, specific activity=27 Ci/mmol), diluted to a 20 nM concentration in PBS (5 nM final concentration). Compounds were solubilized in 100% DMSO (Acros Organics, Cat. #61042-1000) and tested over a range of 7 concentrations (from 0.1 nM to 10 μM). The final concentration of DMSO in the reactions is equal to or less than 0.1%. Total and nonspecific binding was determined in the absence and presence of 10 μM (N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylnaphthalene-1-carboxamide, CAS Registry #1089563-88-1). The total volume of each reaction is 200 μL (20 μL of diluted compounds, 80 μL of [3H]-EMPA diluted in PBS and 100 μL of the cell suspension). Reactions were run for 60 min at room temperature and terminated by filtration through GF/C filter plates (PerkinElmer, Cat. #6005174) presoaked in 0.3% polyethylenimine using the cell harvester (PerkinElmer Filtermate). The plates were washed 3 times by aspirating 30 ml PBS through the plates. Plates were dried in 55° C. oven for 60 min, scintillation fluid was added, and the radioactivity was counted on a Topcount (Packard).
Measurement: Ki = 10000 nM (pChEMBL 5)
Descriptors: MW 407.45, ALogP 2.02, HBA 7, HBD 0, PSA 80.04, QED 0.66
Compound (SMILES): Cc1cc(C)nc(N2CC3CN(C(=O)c4cccc(F)c4-c4ncccn4)CC3C2)n1
InChIKey: FPWNRYVTJLOJGZ-UHFFFAOYSA-N
Target: Orexin/Hypocretin receptor type 1 (SINGLE PROTEIN), Homo sapiens
UniProt: O43613
Assay: Receptor Radioligand Binding Assay: Chinese ovary cells (CHO) stably expressing human orexin 1 receptor (Genebank accession number NM_001526) were grown to confluency in DMEM/F12 (Gibco, Cat #11039), 10% FBS, 1× Pen/Strep, 600 μg/mL G418 media on 150 cm2 tissue culture plates, washed with 5 mM EDTA in PBS (HyClone Dulbecco's Phosphate Buffered Saline 1× with Calcium and Magnesium, Cat # SH30264.01, hereafter referred to simply as PBS) and scraped into 50 ml tubes. After centrifugation (2K×G, 10 min at 4° C.), the supernatant was aspirated and the pellets frozen and stored at −80° C. Cells were resuspended in PBS in the presence of 1 tablet of protease inhibitor cocktail (Roche, Cat. #11836145001) per 50 mL. Each cell pellet from a 15 cm plate was resuspended in 10 mL, stored on ice, and vortexed for 45 sec prior to addition to the reactions. Competition binding experiments in 96 well polypropylene plates were performed using [3H]-SB674042 (Moravek Corporation, specific activity=35.3 Ci/mmol), diluted to a 10 nM concentration in PBS (4 nM final). Compounds were solubilized in 100% DMSO (Acros Organics, Cat. #61042-1000) and tested over a range of 7 concentrations (from 0.1 nM to 10 μM). The final concentration of DMSO in the reactions is equal to or less than 0.1%. Total and nonspecific binding was determined in the absence and presence of 10 μM (1-(6,8-difluoro-2-methylquinolin-4-yl)-3-[4-(dimethylamino)phenyl]urea, CAS Registry #288150-92-5). The total volume of each reaction is 200 μL (20 μL of diluted compounds, 80 μL of [3H]-5B674042 diluted in PBS and 100 μL of the cell suspension). Reactions were run for 60 min at room temperature and terminated by filtration through GF/C filter plates (PerkinElmer, Cat. #6005174) presoaked in 0.3% polyethylenimine using the cell harvester (PerkinElmer Filtermate). The plates were washed 3 times by aspirating 30 ml PBS through the plates. Plates were dried in 55° C. oven for 60 min, scintillation fluid was added, and the radioactivity was counted on a Topcount (Packard).
Measurement: Ki = 18 nM (pChEMBL 7.75)
Descriptors: MW 418.48, ALogP 2.9, HBA 6, HBD 0, PSA 75.11, QED 0.65
Compound (SMILES): COc1ccc(C(=O)N2CC3CN(c4nc(C)cc(C)n4)CC3C2)c(-n2nccn2)c1
InChIKey: ULXUMMWTPGKPRC-UHFFFAOYSA-N
Target: Orexin/Hypocretin receptor type 1 (SINGLE PROTEIN), Homo sapiens
UniProt: O43613
Assay: Receptor Radioligand Binding Assay: Chinese ovary cells (CHO) stably expressing human orexin 1 receptor (Genebank accession number NM_001526) were grown to confluency in DMEM/F12 (Gibco, Cat #11039), 10% FBS, 1× Pen/Strep, 600 μg/mL G418 media on 150 cm2 tissue culture plates, washed with 5 mM EDTA in PBS (HyClone Dulbecco's Phosphate Buffered Saline 1× with Calcium and Magnesium, Cat # SH30264.01, hereafter referred to simply as PBS) and scraped into 50 ml tubes. After centrifugation (2K×G, 10 min at 4° C.), the supernatant was aspirated and the pellets frozen and stored at −80° C. Cells were resuspended in PBS in the presence of 1 tablet of protease inhibitor cocktail (Roche, Cat. #11836145001) per 50 mL. Each cell pellet from a 15 cm plate was resuspended in 10 mL, stored on ice, and vortexed for 45 sec prior to addition to the reactions. Competition binding experiments in 96 well polypropylene plates were performed using [3H]-SB674042 (Moravek Corporation, specific activity=35.3 Ci/mmol), diluted to a 10 nM concentration in PBS (4 nM final). Compounds were solubilized in 100% DMSO (Acros Organics, Cat. #61042-1000) and tested over a range of 7 concentrations (from 0.1 nM to 10 μM). The final concentration of DMSO in the reactions is equal to or less than 0.1%. Total and nonspecific binding was determined in the absence and presence of 10 μM (1-(6,8-difluoro-2-methylquinolin-4-yl)-3-[4-(dimethylamino)phenyl]urea, CAS Registry #288150-92-5). The total volume of each reaction is 200 μL (20 μL of diluted compounds, 80 μL of [3H]-5B674042 diluted in PBS and 100 μL of the cell suspension). Reactions were run for 60 min at room temperature and terminated by filtration through GF/C filter plates (PerkinElmer, Cat. #6005174) presoaked in 0.3% polyethylenimine using the cell harvester (PerkinElmer Filtermate). The plates were washed 3 times by aspirating 30 ml PBS through the plates. Plates were dried in 55° C. oven for 60 min, scintillation fluid was added, and the radioactivity was counted on a Topcount (Packard).
Measurement: Ki = 10 nM (pChEMBL 8)
Descriptors: MW 419.49, ALogP 1.89, HBA 8, HBD 0, PSA 89.27, QED 0.64
Compound (SMILES): COc1cc(Nc2ncc(Br)c(N[C@H](C)[C@H](C)O)n2)ccc1S(C)(=N)=O
InChIKey: GNODSQUZRSUVER-QILFFNKJSA-N
Target: Cyclin-dependent kinase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P06493
Assay: Kinase Assay: Kinase assay using either CDK1, CDK2 or VEGFR-2.
Measurement: IC50 = 3 nM (pChEMBL 8.520000457763672)
Descriptors: MW 444.36, ALogP 3.21, HBA 8, HBD 4, PSA 120.22, QED 0.52
Compound (SMILES): COc1cc(Nc2ncc(Br)c(N[C@H](C)C(C)(C)O)n2)ccc1S(C)(=N)=O
InChIKey: VEMUNZLIOXAWMA-VQLJPOJZSA-N
Target: Cyclin-dependent kinase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P06493
Assay: Kinase Assay: Kinase assay using either CDK1, CDK2 or VEGFR-2.
Measurement: IC50 = 8 nM (pChEMBL 8.100000381469727)
Descriptors: MW 458.38, ALogP 3.6, HBA 8, HBD 4, PSA 120.22, QED 0.5
Compound (SMILES): CCS(=N)(=O)c1ccc(Nc2ncc(Br)c(N[C@H](C)C(C)(C)O)n2)cc1
InChIKey: BIOJVWLNPPOUGW-RRSIMWOXSA-N
Target: Vascular endothelial growth factor receptor 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P35968
Assay: Kinase Assay: Kinase assay using either CDK1, CDK2 or VEGFR-2.
Measurement: IC50 = 79 nM (pChEMBL 7.099999904632568)
Descriptors: MW 442.38, ALogP 3.98, HBA 7, HBD 4, PSA 110.99, QED 0.52
Compound (SMILES): Cc1cc(Nc2ncc(Br)c(N[C@H](C)C(C)(C)O)n2)ccc1S(C)(=N)=O
InChIKey: GKJRCQIJVHMRJB-RRSIMWOXSA-N
Target: Vascular endothelial growth factor receptor 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P35968
Assay: Kinase Assay: Kinase assay using either CDK1, CDK2 or VEGFR-2.
Measurement: IC50 = 66 nM (pChEMBL 7.179999828338623)
Descriptors: MW 442.38, ALogP 3.9, HBA 7, HBD 4, PSA 110.99, QED 0.54
Compound (SMILES): CNc1nc2ccccc2n1-c1nc(N2CCOC[C@H]2C)cc(C2([S@](C)(=N)=O)CC2)n1
InChIKey: JESNSKPPMWEWAT-JKGBWWFKSA-N
Target: Cytochrome P450 1A2 (SINGLE PROTEIN), Homo sapiens
UniProt: P05177
Assay: Inhibition of CYP1A2 in human liver microsomes using midazolam as substrate preincubated for 15 mins followed by substrate addition and measured after 30 mins in presence of NADPH by LC-MS analysis
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 441.56, ALogP 2.75, HBA 9, HBD 2, PSA 109.02, QED 0.63
Compound (SMILES): CC(=O)NCC[C@@H]1CCc2ccc3nc(C)oc3c21
InChIKey: CCRUCMHMQXUZAT-LBPRGKRZSA-N
Target: Melatonin receptor type 1B (SINGLE PROTEIN), Homo sapiens
UniProt: P49286
Assay: Agonist activity at human MT2 expressed in CHO-K1 cells assessed as inhibition of forskolin-induced cAMP accumulation incubated for 30 mins by AlphaScreen assay
Measurement: EC50 = 0.51 nM (pChEMBL 9.289999961853027)
Descriptors: MW 258.32, ALogP 2.69, HBA 3, HBD 1, PSA 55.13, QED 0.92
Compound (SMILES): Cc1nc(-c2c(F)cc(Cl)cc2-c2cnc3c(c2)CCC3NC(=O)C2(NC(=O)c3ccnnc3)CC2)no1
InChIKey: VKQZQIDNZZTHCQ-UHFFFAOYSA-N
Target: B1 bradykinin receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P46663
Assay: Calcium Mobilization Assay: Calcium mobilization assay using Bradykinin-1 receptor.
Measurement: IC50 = 0.2 nM (pChEMBL 9.699999809265137)
Descriptors: MW 533.95, ALogP 3.76, HBA 8, HBD 2, PSA 135.79, QED 0.38
Compound (SMILES): Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CC[C@@H](N)[C@H](F)CC1
InChIKey: NHXVGMQFCYBLTL-ZWNOBZJWSA-N
Target: Cytochrome P450 3A4 (SINGLE PROTEIN), Homo sapiens
UniProt: P08684
Assay: Time dependent inhibition of CYP3A4 (unknown origin) using testosterone as substrate
Measurement: Ki = 1120 nM (pChEMBL 5.949999809265137)
Descriptors: MW 465.51, ALogP 2.92, HBA 8, HBD 3, PSA 115.09, QED 0.55
Compound (SMILES): Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1C1CCC(N)CC(C)(O)C1
InChIKey: CATWESQSWJEUNP-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase pim-1 (SINGLE PROTEIN), Homo sapiens
UniProt: P11309
Assay: Pim Kinase Binding Activity: PIM-1, -2, and -3 enzymes were generated as fusion proteins expressed in bacteria and purified by IMAC column chromatography (Sun, X., Chiu, J. F., and He, Q. Y. (2005) Expert Rev. Proteomics, 2:649-657). A fluorescent-labeled Pim-specific peptide substrate, was custom synthesized by American Peptide Company (Sunnyvale, Calif.). A fluorescent-labeled Pim-specific peptide substrate, was custom synthesized by American Peptide Company (Sunnyvale, Calif.). Reaction Buffer contained 10 mM HEPES, pH 7.2, 10 mM MgCl2, 0.01% Tween 20, 2 mM DTT. Termination Buffer contained 190 mM HEPES, pH 7.2, 0.015% Brij-35, 0.2% Coating Reagent 3 (Caliper Life Sciences, Hopkinton, Mass.), 20 mM EDTA. Separation Buffer contained 100 mM HEPES, pH 7.2, 0.015% Brij-35, 0.1% Coating Reagent 3, 1:200 Coating Reagent 8 (Caliper Life Sciences, Hopkinton, Mass.), 10 mM EDTA and 5% DMSO.
Measurement: Ki = 1.55 nM (pChEMBL 8.8100004196167)
Descriptors: MW 476.55, ALogP 3.39, HBA 8, HBD 4, PSA 132.08, QED 0.43
Compound (SMILES): Cc1cc(COc2ccc(S(=O)(=O)NC[C@@H](C(=O)NO)N3CCN(S(C)(=O)=O)CC3)cc2)c2ccccc2n1
InChIKey: IVLLKNCAVYHIFI-DEOSSOPVSA-N
Target: Disintegrin and metalloproteinase domain-containing protein 9 (SINGLE PROTEIN), Homo sapiens
UniProt: Q13443
Assay: Inhibition Assay: The molecules are dose-response tested on the following enzymes: MMP1, MMP3, MMP9, ADAM9 and ADAM10, according to the same protocol as that described for the TACE enzyme in example 28, but with different substrates (MMP R&D systems, reference: P126-990, and ADAM R&D systems, reference: ES003).
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 577.69, ALogP 0.85, HBA 9, HBD 3, PSA 158.24, QED 0.23
Compound (SMILES): Cc1cc(COc2ccc(S(=O)(=O)NC[C@@H](C(=O)NO)N3CCN(Cc4ccc(F)cc4)CC3)cc2)c2ccccc2n1
InChIKey: UWCNFKCKFSEPKW-PMERELPUSA-N
Target: Disintegrin and metalloproteinase domain-containing protein 17 (SINGLE PROTEIN), Homo sapiens
UniProt: P78536
Assay: Enzymatic Assay : The TACE enzyme is an internal production (carried out according to the publication protein Eng Des Sel 2006, 19, 155-161) and is added so as to have a signal equivalent to 6 times the background noise in 2 h at 37° C. The reaction is carried out in 50 mM Tris buffered medium containing 4% glycerol, pH 7.4. The fluorescent substrate is MCA-Pro-Leu-Ala-Val-(Dpa)-Arg-Ser-Ser-Arg-NH2 (R&D systems, reference: ES003). The substrate is cleaved by the enzyme between the alanine and the valine, thus releasing a fluorescent peptide (excitation: 320 nm, emission: 420 nm). The substrate is used at 40 μM. The reaction is carried out in a final volume of 10 μl (4 μl inhibitor, 4 μl substrate, 2 μl enzyme) in a low volume 384-well plate (Corning reference: 3676). The plate is incubated at ambient temperature for 2 h, and then read by fluorescence on a Pherastar reader (BMG labtech).
Measurement: IC50 = 67 nM (pChEMBL 7.170000076293945)
Descriptors: MW 607.71, ALogP 3.23, HBA 8, HBD 3, PSA 124.1, QED 0.18
Compound (SMILES): CCN1CCN([C@@H](CNS(=O)(=O)c2ccc(OCc3cc(C)nc4ccccc34)cc2)C(=O)NO)CC1
InChIKey: UFNKXVJYCDHZQW-VWLOTQADSA-N
Target: Disintegrin and metalloproteinase domain-containing protein 10 (SINGLE PROTEIN), Homo sapiens
UniProt: O14672
Assay: Inhibition Assay: The molecules are dose-response tested on the following enzymes: MMP1, MMP3, MMP9, ADAM9 and ADAM10, according to the same protocol as that described for the TACE enzyme in example 28, but with different substrates (MMP R&D systems, reference: P126-990, and ADAM R&D systems, reference: ES003).
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 527.65, ALogP 1.91, HBA 8, HBD 3, PSA 124.1, QED 0.27
Compound (SMILES): Cc1ccc(CN2CCN([C@@H](CNS(=O)(=O)c3ccc(OCc4cc(C)nc5ccccc45)cc3)C(=O)NO)CC2)cc1
InChIKey: OEKBBQNVZPGHFU-HKBQPEDESA-N
Target: Disintegrin and metalloproteinase domain-containing protein 10 (SINGLE PROTEIN), Homo sapiens
UniProt: O14672
Assay: Inhibition Assay: The molecules are dose-response tested on the following enzymes: MMP1, MMP3, MMP9, ADAM9 and ADAM10, according to the same protocol as that described for the TACE enzyme in example 28, but with different substrates (MMP R&D systems, reference: P126-990, and ADAM R&D systems, reference: ES003).
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 603.75, ALogP 3.4, HBA 8, HBD 3, PSA 124.1, QED 0.18
Compound (SMILES): Cc1cc(COc2ccc(S(=O)(=O)NC[C@@H](C(=O)NO)N3CCN(C(=O)C(C)C)CC3)cc2)c2ccccc2n1
InChIKey: NVPQXUAYORUQIU-SANMLTNESA-N
Target: Disintegrin and metalloproteinase domain-containing protein 10 (SINGLE PROTEIN), Homo sapiens
UniProt: O14672
Assay: Inhibition Assay: The molecules are dose-response tested on the following enzymes: MMP1, MMP3, MMP9, ADAM9 and ADAM10, according to the same protocol as that described for the TACE enzyme in example 28, but with different substrates (MMP R&D systems, reference: P126-990, and ADAM R&D systems, reference: ES003).
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 569.68, ALogP 2.07, HBA 8, HBD 3, PSA 141.17, QED 0.25
Compound (SMILES): Cc1cc(COc2ccc(S(=O)(=O)NC[C@@H](C(=O)NO)N3CCN(S(=O)(=O)CC(C)C)CC3)cc2)c2ccccc2n1
InChIKey: IUVIWMVVODOSQU-MHZLTWQESA-N
Target: Disintegrin and metalloproteinase domain-containing protein 10 (SINGLE PROTEIN), Homo sapiens
UniProt: O14672
Assay: Inhibition Assay: The molecules are dose-response tested on the following enzymes: MMP1, MMP3, MMP9, ADAM9 and ADAM10, according to the same protocol as that described for the TACE enzyme in example 28, but with different substrates (MMP R&D systems, reference: P126-990, and ADAM R&D systems, reference: ES003).
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 619.77, ALogP 1.88, HBA 9, HBD 3, PSA 158.24, QED 0.2
Compound (SMILES): Cc1cc(COc2ccc(S(=O)(=O)NC[C@@H](C(=O)NO)N3CCN(S(=O)(=O)C(C)C)CC3)cc2)c2ccccc2n1
InChIKey: AHKGXKHDKHAJDE-SANMLTNESA-N
Target: Disintegrin and metalloproteinase domain-containing protein 10 (SINGLE PROTEIN), Homo sapiens
UniProt: O14672
Assay: Inhibition Assay: The molecules are dose-response tested on the following enzymes: MMP1, MMP3, MMP9, ADAM9 and ADAM10, according to the same protocol as that described for the TACE enzyme in example 28, but with different substrates (MMP R&D systems, reference: P126-990, and ADAM R&D systems, reference: ES003).
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 605.74, ALogP 1.63, HBA 9, HBD 3, PSA 158.24, QED 0.22
Compound (SMILES): Cc1cc(C)nc(N2CC3CN(C(=O)c4ccccc4-n4nccn4)CC3C2)n1
InChIKey: LCDKKZMNYHMDCH-UHFFFAOYSA-N
Target: Orexin receptor type 2 (SINGLE PROTEIN), Homo sapiens
UniProt: O43614
Assay: Biological Assay: The in vitro affinity of the compounds for the human orexin-1 and orexin-2 receptors was determined by competitive radioligand binding using [3H]SB SB674042 (1-(5-(2-fluoro-phenyl)-2-methyl-thiazol-4-yl)-1-((S)-2-(5-phenyl-(1,3,4)oxadiazol-2-ylmethyl)-pyrrolidin-1-yl)-methanone) (Langmead et al., British Journal of Pharmacology 2004, 141:340-346) and [3H]EMPA (N-ethyl-2[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-3-ylmethyl acetamide) (Malherbe et al., British Journal of Pharmacology, 2009, 156(8), 1326-1341), respectively. The in vitro functional antagonism of the compounds on the human orexin-1 and orexin-2 receptors was determined using fluorometric imaging plate reader (FLIPR) based calcium assays.
Measurement: Ki = 12 nM (pChEMBL 7.920000076293945)
Descriptors: MW 389.46, ALogP 1.88, HBA 7, HBD 0, PSA 80.04, QED 0.68
Compound (SMILES): Cc1cc(C)nc(N2CC3CN(C(=O)c4cccc(F)c4-c4ncccn4)CC3C2)n1
InChIKey: FPWNRYVTJLOJGZ-UHFFFAOYSA-N
Target: Orexin receptor type 2 (SINGLE PROTEIN), Homo sapiens
UniProt: O43614
Assay: Receptor Radioligand Binding Assay: HEK293 stably expressing human orexin-2 receptor (Genebank accession number NM_001526) were grown to confluency in DMEM/F12 (Gibco, Cat #11039), in DMEM, 10% FBS, 1× Pen/Strep, 1× NaPyruvate, 1×HEPES, 600 ug/ml G418 media on 150 cm2 tissue culture plates, washed with 5 mM EDTA in PBS (HyClone Dulbecco's Phosphate Buffered Saline 1× with Calcium and Magnesium, Cat # SH30264.01, hereafter referred to simply as PBS) and scraped into 50 ml tubes. After centrifugation (2K×G, 10 min at 4° C.), the supernatant was aspirated and the pellets frozen and stored at −80° C. Cells were resuspended in PBS in the presence of 1 tablet of protease inhibitor cocktail (Roche, Cat. #11836145001) per 50 mL. Each cell pellet from a 15 cm plate was resuspended in 10 mL, stored on ice, and vortexed for 45 sec just prior to addition to the reactions. Competition binding experiments in 96 well polypropylene plates were performed using [3H]-EMPA (Moravek Corporation, specific activity=27 Ci/mmol), diluted to a 20 nM concentration in PBS (5 nM final concentration). Compounds were solubilized in 100% DMSO (Acros Organics, Cat. #61042-1000) and tested over a range of 7 concentrations (from 0.1 nM to 10 μM). The final concentration of DMSO in the reactions is equal to or less than 0.1%. Total and nonspecific binding was determined in the absence and presence of 10 μM (N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylnaphthalene-1-carboxamide, CAS Registry #1089563-88-1). The total volume of each reaction is 200 μL (20 μL of diluted compounds, 80 μL of [3H]-EMPA diluted in PBS and 100 μL of the cell suspension). Reactions were run for 60 min at room temperature and terminated by filtration through GF/C filter plates (PerkinElmer, Cat. #6005174) presoaked in 0.3% polyethylenimine using the cell harvester (PerkinElmer Filtermate). The plates were washed 3 times by aspirating 30 ml PBS through the plates. Plates were dried in 55° C. oven for 60 min, scintillation fluid was added, and the radioactivity was counted on a Topcount (Packard).
Measurement: Ki = 1876 nM (pChEMBL 5.730000019073486)
Descriptors: MW 418.48, ALogP 2.9, HBA 6, HBD 0, PSA 75.11, QED 0.65
Compound (SMILES): COc1ccc(C(=O)N2CC3CN(c4nc(C)cc(C)n4)CC3C2)c(-n2nccn2)c1
InChIKey: ULXUMMWTPGKPRC-UHFFFAOYSA-N
Target: Orexin receptor type 2 (SINGLE PROTEIN), Homo sapiens
UniProt: O43614
Assay: Receptor Radioligand Binding Assay: HEK293 stably expressing human orexin-2 receptor (Genebank accession number NM_001526) were grown to confluency in DMEM/F12 (Gibco, Cat #11039), in DMEM, 10% FBS, 1× Pen/Strep, 1× NaPyruvate, 1×HEPES, 600 ug/ml G418 media on 150 cm2 tissue culture plates, washed with 5 mM EDTA in PBS (HyClone Dulbecco's Phosphate Buffered Saline 1× with Calcium and Magnesium, Cat # SH30264.01, hereafter referred to simply as PBS) and scraped into 50 ml tubes. After centrifugation (2K×G, 10 min at 4° C.), the supernatant was aspirated and the pellets frozen and stored at −80° C. Cells were resuspended in PBS in the presence of 1 tablet of protease inhibitor cocktail (Roche, Cat. #11836145001) per 50 mL. Each cell pellet from a 15 cm plate was resuspended in 10 mL, stored on ice, and vortexed for 45 sec just prior to addition to the reactions. Competition binding experiments in 96 well polypropylene plates were performed using [3H]-EMPA (Moravek Corporation, specific activity=27 Ci/mmol), diluted to a 20 nM concentration in PBS (5 nM final concentration). Compounds were solubilized in 100% DMSO (Acros Organics, Cat. #61042-1000) and tested over a range of 7 concentrations (from 0.1 nM to 10 μM). The final concentration of DMSO in the reactions is equal to or less than 0.1%. Total and nonspecific binding was determined in the absence and presence of 10 μM (N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylnaphthalene-1-carboxamide, CAS Registry #1089563-88-1). The total volume of each reaction is 200 μL (20 μL of diluted compounds, 80 μL of [3H]-EMPA diluted in PBS and 100 μL of the cell suspension). Reactions were run for 60 min at room temperature and terminated by filtration through GF/C filter plates (PerkinElmer, Cat. #6005174) presoaked in 0.3% polyethylenimine using the cell harvester (PerkinElmer Filtermate). The plates were washed 3 times by aspirating 30 ml PBS through the plates. Plates were dried in 55° C. oven for 60 min, scintillation fluid was added, and the radioactivity was counted on a Topcount (Packard).
Measurement: Ki = 1385 nM (pChEMBL 5.860000133514404)
Descriptors: MW 419.49, ALogP 1.89, HBA 8, HBD 0, PSA 89.27, QED 0.64
Compound (SMILES): CNc1nc2ccccc2n1-c1nc(N2CCOC[C@H]2C)cc(C2([S@](C)(=N)=O)CC2)n1
InChIKey: JESNSKPPMWEWAT-JKGBWWFKSA-N
Target: Cytochrome P450 2C19 (SINGLE PROTEIN), Homo sapiens
UniProt: P33261
Assay: Inhibition of CYP2C19 in human liver microsomes using midazolam as substrate preincubated for 15 mins followed by substrate addition and measured after 30 mins in presence of NADPH by LC-MS analysis
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 441.56, ALogP 2.75, HBA 9, HBD 2, PSA 109.02, QED 0.63
Compound (SMILES): Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CC[C@@H](N)[C@H](F)CC1
InChIKey: NHXVGMQFCYBLTL-ZWNOBZJWSA-N
Target: Alpha-1A adrenergic receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P35348
Assay: Antagonist activity at alpha 1a adrenergic receptor (unknown origin)
Measurement: IC50 = 2500 nM (pChEMBL 5.599999904632568)
Descriptors: MW 465.51, ALogP 2.92, HBA 8, HBD 3, PSA 115.09, QED 0.55
Compound (SMILES): Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1C1CCC(N)CC(C)(O)C1
InChIKey: CATWESQSWJEUNP-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase pim-1 (SINGLE PROTEIN), Homo sapiens
UniProt: P11309
Assay: Pim Kinase Binding Activity: PIM-1, -2, and -3 enzymes were generated as fusion proteins expressed in bacteria and purified by IMAC column chromatography (Sun, X., Chiu, J. F., and He, Q. Y. (2005) Expert Rev. Proteomics, 2:649-657). A fluorescent-labeled Pim-specific peptide substrate, was custom synthesized by American Peptide Company (Sunnyvale, Calif.). A fluorescent-labeled Pim-specific peptide substrate, was custom synthesized by American Peptide Company (Sunnyvale, Calif.). Reaction Buffer contained 10 mM HEPES, pH 7.2, 10 mM MgCl2, 0.01% Tween 20, 2 mM DTT. Termination Buffer contained 190 mM HEPES, pH 7.2, 0.015% Brij-35, 0.2% Coating Reagent 3 (Caliper Life Sciences, Hopkinton, Mass.), 20 mM EDTA. Separation Buffer contained 100 mM HEPES, pH 7.2, 0.015% Brij-35, 0.1% Coating Reagent 3, 1:200 Coating Reagent 8 (Caliper Life Sciences, Hopkinton, Mass.), 10 mM EDTA and 5% DMSO.
Measurement: Ki = 0.108 nM (pChEMBL 9.970000267028809)
Descriptors: MW 476.55, ALogP 3.39, HBA 8, HBD 4, PSA 132.08, QED 0.43
Compound (SMILES): Cc1cc(COc2ccc(S(=O)(=O)NC[C@@H](C(=O)NO)N3CCN(S(C)(=O)=O)CC3)cc2)c2ccccc2n1
InChIKey: IVLLKNCAVYHIFI-DEOSSOPVSA-N
Target: Disintegrin and metalloproteinase domain-containing protein 10 (SINGLE PROTEIN), Homo sapiens
UniProt: O14672
Assay: Inhibition Assay: The molecules are dose-response tested on the following enzymes: MMP1, MMP3, MMP9, ADAM9 and ADAM10, according to the same protocol as that described for the TACE enzyme in example 28, but with different substrates (MMP R&D systems, reference: P126-990, and ADAM R&D systems, reference: ES003).
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 577.69, ALogP 0.85, HBA 9, HBD 3, PSA 158.24, QED 0.23