lovingscience/chembl-v37-raw-activities huggingface dataset:
Compound (SMILES): COCc1nn(Cc2ccc(Cn3ccccc3=O)cc2)cc1C(=O)NCc1nccc(OC)c1F
InChIKey: KGMPDQIYDKKXRD-UHFFFAOYSA-N
Target: Cytochrome P450 3A4 (SINGLE PROTEIN), Homo sapiens
UniProt: P08684
Assay: Inhibition of CYP3A4 in human liver microsomes assessed as reduction in 6beta-hydroxytestosterone metabolite formation using testosterone as substrate incubated for 30 mins in presence of NADPH by LC-MS/MS analysis
Measurement: IC50 > 25000 nM (pChEMBL 4.6020002365112305)
Descriptors: MW 491.52, ALogP 2.76, HBA 8, HBD 1, PSA 100.27, QED 0.37
Compound (SMILES): CC1(C)Cn2nc(-c3ccc(F)cn3)c(-c3ccnc4[nH]ncc34)c2CO1
InChIKey: WZMIWVZGYMKUDV-UHFFFAOYSA-N
Target: Casein kinase I isoform epsilon (SINGLE PROTEIN), Homo sapiens
UniProt: P49674
Assay: Inhibition of CK1 epsilon (unknown origin)
Measurement: IC50 = 93 nM (pChEMBL 7.03000020980835)
Descriptors: MW 364.38, ALogP 3.33, HBA 6, HBD 1, PSA 81.51, QED 0.59
Compound (SMILES): COc1ccc2nc3ccc(OC)cc3c(SCCCN)c2c1
InChIKey: ZFOMCSNUEHMROO-UHFFFAOYSA-N
Target: Dual specificity tyrosine-phosphorylation-regulated kinase 1B (SINGLE PROTEIN), Homo sapiens
UniProt: Q9Y463
Assay: Inhibition of recombinant human DYRK1B expressed in Sf9 insect cells incubated for 60 mins in presence of ATP and [gamma33-P] ATP by radiometric scintillation counter analysis
Measurement: IC50 = 2113 nM (pChEMBL 5.670000076293945)
Descriptors: MW 328.44, ALogP 3.85, HBA 5, HBD 1, PSA 57.37, QED 0.42
Compound (SMILES): CC(C)C(=O)Nc1ncc(C(=O)NCCN(Cc2ccccc2)C(=O)c2ccc(S(=O)(=O)Nc3ccccc3)cc2)s1
InChIKey: YVPYJSSYGACUSE-UHFFFAOYSA-N
Target: LIM domain kinase 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P53671
Assay: Inhibition of recombinant LIMK2 (347 to 659 residues) (unknown origin) incubated for 45 mins followed by ATP addition measured after 180 mins by RapidFire Mass Spectrometry kinase assay
Measurement: IC50 = 5.495 nM (pChEMBL 8.260000228881836)
Descriptors: MW 605.74, ALogP 4.61, HBA 7, HBD 3, PSA 137.57, QED 0.22
Compound (SMILES): Cc1ccc(C(=O)Nc2ccc3c(c2)C(F)(F)C[C@@H]3N2CCN(C)CC2)cc1C#Cc1cnc2cccnn12
InChIKey: BPLVEFPXYUJTQJ-MHZLTWQESA-N
Target: Platelet-derived growth factor receptor alpha (SINGLE PROTEIN), Homo sapiens
UniProt: P16234
Assay: Inhibition of human PDGFRa using poly [Glu:Tyr] as substrate incubated for 30 mins followed by 33P-ATP addition and measured after 2 hrs by liquid scintillation counter method
Measurement: IC50 < 10 nM (pChEMBL 8)
Descriptors: MW 526.59, ALogP 4.47, HBA 6, HBD 1, PSA 65.77, QED 0.4
Compound (SMILES): C=CC(=O)Nc1cc(N2CCN(C)CC2)ccc1Nc1ncc2c(n1)-n1ccc(C(=O)Nc3c(CC)cccc3CC)c1CC2
InChIKey: QMTKZAHTDPRIFJ-UHFFFAOYSA-N
Target: Dual specificity protein kinase TTK (SINGLE PROTEIN), Homo sapiens
UniProt: P33981
Assay: Inhibition of recombinant human full length N-terminal GST-fused MPS1 (1 to 857 residues) using histone H3 as substrate by TR-FRET assay
Measurement: IC50 = 13 nM (pChEMBL 7.889999866485596)
Descriptors: MW 604.76, ALogP 5.36, HBA 8, HBD 3, PSA 107.42, QED 0.22
Compound (SMILES): O=C(NCCCn1ccnc1)c1cc2nc(-c3ccccc3)cc(-c3ccccc3)n2n1
InChIKey: RIGHCDSORZCRDE-UHFFFAOYSA-N
Target: Alpha-2A adrenergic receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P08913
Assay: GPCRScan assay: inhibition of Alpha2A
Measurement: Ki = 3801.89 nM (pChEMBL 5.420000076293945)
Descriptors: MW 422.49, ALogP 4.08, HBA 6, HBD 1, PSA 77.11, QED 0.4
Compound (SMILES): CCNCCc1ccc(Cl)c(-c2ccccc2OC)c1.Cl
InChIKey: SXOXLJQRLIFVCQ-UHFFFAOYSA-N
Target: 5-hydroxytryptamine receptor 2C (SINGLE PROTEIN), Homo sapiens
UniProt: P28335
Assay: Binding affinity to 5-HT2CR (unknown origin)
Measurement: Ki > 10000 nM (pChEMBL 5)
Descriptors: MW 289.81, ALogP 4.17, HBA 2, HBD 1, PSA 21.26, QED 0.81
Compound (SMILES): CCCN(CCC)CCc1ccc(Cl)c(-c2ccccc2OC)c1
InChIKey: IOJLDPRGTSPRBT-UHFFFAOYSA-N
Target: 5-hydroxytryptamine receptor 2C (SINGLE PROTEIN), Homo sapiens
UniProt: P28335
Assay: Binding affinity to 5-HT2CR (unknown origin)
Measurement: Ki > 10000 nM (pChEMBL 5)
Descriptors: MW 345.91, ALogP 5.68, HBA 2, HBD 0, PSA 12.47, QED 0.58
Compound (SMILES): CCCCNCc1ccc(Cl)c(-c2ccccc2OC)c1
InChIKey: PKQCAZLGEGUDLP-UHFFFAOYSA-N
Target: 5-hydroxytryptamine receptor 5A (SINGLE PROTEIN), Homo sapiens
UniProt: P47898
Assay: Binding affinity to 5-HT5AR (unknown origin)
Measurement: Ki = 360 nM (pChEMBL 6.440000057220459)
Descriptors: MW 303.83, ALogP 4.91, HBA 2, HBD 1, PSA 21.26, QED 0.73
Compound (SMILES): C[C@@H](c1cc(Cl)cc(Cl)c1)N1CCC(COc2cc(F)c(C(=O)NS(C)(=O)=O)cc2C2CC2)CC1
InChIKey: SXOAHIZWCZOILH-HNNXBMFYSA-N
Target: Sodium channel protein type 9 subunit alpha/beta-1/beta-2 (PROTEIN COMPLEX), Homo sapiens
UniProt: O60939
Assay: Inhibition of human Nav1.7/beta1/2 transfected in HEK293-A cells assessed as inhibition of channel current incubated for 5.5 mins by high-throughput electrophysiology system analysis
Measurement: IC50 = 0.6 nM (pChEMBL 9.220000267028809)
Descriptors: MW 543.49, ALogP 5.55, HBA 5, HBD 1, PSA 75.71, QED 0.47
Compound (SMILES): C[C@@H](COCCC(=O)N1CCN(c2ncc(C(F)(F)F)cn2)CC1)Nc1cn[nH]c(=O)c1C(F)(F)F
InChIKey: UQZCQKXJAXKZQH-LBPRGKRZSA-N
Target: Poly [ADP-ribose] polymerase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P09874
Assay: Inhibition of N-terminal GST tagged human recombinant PARP1 (2 to 1014 residues) preincubated for 10 mins followed by PARP substrate addition and measured after 30 mins by fluorescence based analysis
Measurement: IC50 = 111 nM (pChEMBL 6.960000038146973)
Descriptors: MW 523.44, ALogP 2.15, HBA 8, HBD 2, PSA 116.34, QED 0.4
Compound (SMILES): Cc1n[nH]c(C)c1-c1cnn(C2(CC#N)CN(c3cc(F)c(C(=O)N[C@@H](C)C(F)(F)F)cc3F)C2)c1
InChIKey: MSGYSFWCPOBHEV-AWEZNQCLSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (SINGLE PROTEIN), Homo sapiens
UniProt: O00329
Assay: PI3Kdelta Scintillation Proximity Assay: [γ-33P]ATP (10 mCi/mL) was purchased from PerkinElmer (Waltham, Mass.). Lipid kinase substrate, D-myo-Phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2)D (+)-sn-1,2-di-O-octanoylglyceryl, 3-O-phospho linked (PIP2), CAS 204858-53-7, was purchased from Echelon Biosciences (Salt Lake City, Utah). PI3Kδ (p110δ/p85α) was purchased from Millipore (Bedford, Mass.). ATP, MgCl2, DTT, EDTA, MOPS and CHAPS were purchased from SigmaAldrich (St. Louis, Mo.). Wheat Germ Agglutinin (WGA) YSi SPA Scintillation Beads was purchased from GE healthcare life sciences (Piscataway, N.J.). The kinase reaction was conducted in polystyrene 384-well matrix white plate from Thermo Fisher Scientific in a final volume of 25 μL. Inhibitors were first diluted serially in DMSO and added to the plate wells before the addition of other reaction components. The final concentration of DMSO in the assay was 0.5%. The PI3K assays were carried out at room temperature in 20 mM MOPS, pH 6.7, 10 mM MgCl2, 5 mM DTT and CHAPS 0.03%. Reactions were initiated by the addition of ATP, the final reaction mixture consisted of 20 μM PIP2, 20 μM ATP, 0.2 μCi [γ-33P] ATP, 4 nM PI3Kδ. Reactions were incubated for 210 min and terminated by the addition of 40 μL SPA beads suspended in quench buffer: 150 mM potassium phosphate pH 8.0, 20% glycerol. 25 mM EDTA, 400 μM ATP. The final concentration of SPA beads was 1.0 mg/mL. After the plate sealing, plates were shaken overnight at room temperature and centrifuged at 1800 rpm for 10 minutes, the radioactivity of the product was determined by scintillation counting on Topcount (PerkinElmer). IC50 determination was performed by fitting the curve of percent control activity versus the log of the inhibitor concentration using the GraphPad Prism 3.0 software.
Measurement: IC50 = 250 nM (pChEMBL 6.599999904632568)
Descriptors: MW 507.47, ALogP 3.98, HBA 6, HBD 2, PSA 102.63, QED 0.49
Compound (SMILES): CC(C)c1c2cc(-c3nc(Nc4ccc(N5CCNCC5)cn4)ncc3F)ccc2nn1C
InChIKey: LLFOBMRPWNABCB-UHFFFAOYSA-N
Target: Cyclin-dependent kinase 5/CDK5 activator 1 (PROTEIN COMPLEX), Homo sapiens
UniProt: Q15078
Assay: Inhibition of CDK5/p25 (unknown origin) in presence of 33P-gamma-ATP by scintillation counting method
Measurement: IC50 = 35.3 nM (pChEMBL 7.449999809265137)
Descriptors: MW 446.53, ALogP 3.84, HBA 8, HBD 2, PSA 83.79, QED 0.48
Compound (SMILES): C[C@H](CC[C@](C)(O)C(F)(F)F)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@](C)(O)CC[C@]4(C)[C@H]3CC[C@]12C
InChIKey: BVBRUQYHUXKZMQ-JNVAYQLDSA-N
Target: Voltage-gated inwardly rectifying potassium channel KCNH2 (SINGLE PROTEIN), Homo sapiens
UniProt: Q12809
Assay: Inhibition of human ERG
Measurement: IC50 > 30000 nM (pChEMBL 4.5229997634887695)
Descriptors: MW 456.63, ALogP 7.05, HBA 2, HBD 2, PSA 40.46, QED 0.45
Compound (SMILES): CO[C@@H]1CCN(c2nccc(Nc3cc4c(C(C)C)ccc(N5C[C@H](CS(C)(=O)=O)[C@H]5C)c4cn3)n2)C[C@@H]1F
InChIKey: LIMFPAAAIVQRRD-BCGVJQADSA-N
Target: Epidermal growth factor receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P00533
Assay: Inhibition of EGFR ex19del/T790M/C797S triple mutant (unknown origin) expressed in mouse BaF3 cells assessed as inhibition of protein phosphorylation
Measurement: IC50 = 40 nM (pChEMBL 7.400000095367432)
Descriptors: MW 556.71, ALogP 4.32, HBA 9, HBD 1, PSA 100.55, QED 0.43
Compound (SMILES): COC[C@H](NC(=O)c1ccn(S(C)(=O)=O)c1)C(=O)Nc1nc(-c2cccc(N3C[C@@H](C)O[C@@H](C)C3)n2)cs1
InChIKey: JBLQNFBXKOAIHG-FCEWJHQRSA-N
Target: Cytochrome P450 3A4 (SINGLE PROTEIN), Homo sapiens
UniProt: P08684
Assay: Inhibition of CYP3A4 (unknown origin) using midazolam as substrate
Measurement: IC50 > 50000 nM (pChEMBL 4.301000118255615)
Descriptors: MW 562.67, ALogP 1.81, HBA 11, HBD 2, PSA 144.75, QED 0.4
Compound (SMILES): Cc1nc(-c2cnc(NC(C)C)n(C)c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
InChIKey: TVGAHWWPABTBCX-UHFFFAOYSA-N
Target: Macrophage colony-stimulating factor 1 receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P07333
Assay: Inhibition of CSF1R (unknown origin) in presence of 4 mM ATP measured by cell-based spectrophotometric assay
Measurement: IC50 = 3 nM (pChEMBL 8.520000457763672)
Descriptors: MW 431.5, ALogP 3.56, HBA 9, HBD 1, PSA 99.75, QED 0.5
Compound (SMILES): C[C@@H](N)c1cc(Cl)ccc1Cn1c(=S)[nH]c(=O)c2[nH]ccc21
InChIKey: BHKKSKOHRFHHIN-MRVPVSSYSA-N
Target: Cytochrome P450 3A4 (SINGLE PROTEIN), Homo sapiens
UniProt: P08684
Assay: Competitive inhibition of human recombinant CYP3A4 using coumarin as substrate preincubated with enzyme for 10 mins followed by NADPH addition and measured after 20 to 50 mins by fluorescence based method
Measurement: IC50 = 6000 nM (pChEMBL 5.21999979019165)
Descriptors: MW 334.83, ALogP 3.11, HBA 4, HBD 3, PSA 79.6, QED 0.64
Compound (SMILES): CCc1cc2ncc(CN3CCN(c4ccc(C(=O)NC)nc4)CC3)cc2[nH]c1=O
InChIKey: WQAVGRAETZEADU-UHFFFAOYSA-N
Target: Poly [ADP-ribose] polymerase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P09874
Assay: Binding affinity to CM5 chip-immobilized GST-tagged PARP1 (unknown origin) assessed as dissociation constant by SPR analysis
Measurement: Kd = 0.55 nM (pChEMBL 9.260000228881836)
Descriptors: MW 406.49, ALogP 1.56, HBA 6, HBD 2, PSA 94.22, QED 0.67
Compound (SMILES): CNC(=O)c1ccc(N2CCN(Cc3ccc4nc(C)c(=O)[nH]c4c3F)CC2)c(F)n1
InChIKey: WXRCLFFPZXJCLS-UHFFFAOYSA-N
Target: Poly [ADP-ribose] polymerase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P09874
Assay: Inhibition of PARP1 (unknown origin) assessed as increase in DNA trapping activity measured after 180 mins by fluorescence anisotropy binding assay
Measurement: EC50 = 296.6 nM (pChEMBL 6.53000020980835)
Descriptors: MW 428.44, ALogP 1.59, HBA 6, HBD 2, PSA 94.22, QED 0.61
Compound (SMILES): CC(=O)N1CCN([C@H]2CCC[C@@H](NC(=O)c3cc4c(F)ccc(C)c4[nH]3)C2)CC1
InChIKey: PGNLXEBQMQHFNK-SJORKVTESA-N
Target: 5-hydroxytryptamine receptor 1B (SINGLE PROTEIN), Homo sapiens
UniProt: P28222
Assay: Agonist activity at 5-HT1B receptor (unknown origin)
Measurement: IC50 = 3200 nM (pChEMBL 5.5)
Descriptors: MW 400.5, ALogP 2.82, HBA 3, HBD 2, PSA 68.44, QED 0.83
Compound (SMILES): COCc1nn(Cc2ccc(Cn3ccccc3=O)cc2)cc1C(=O)NCc1nccc(OC)c1F
InChIKey: KGMPDQIYDKKXRD-UHFFFAOYSA-N
Target: Plasma kallikrein (SINGLE PROTEIN), Homo sapiens
UniProt: P03952
Assay: Inhibition of DXS induced human whole plasma kallikrein using H-D-Pro-Phe-Arg-AFC as substrate preincubated for 5 mins followed by DXS stimulation by fluorometer analysis
Measurement: IC50 = 54 nM (pChEMBL 7.269999980926514)
Descriptors: MW 491.52, ALogP 2.76, HBA 8, HBD 1, PSA 100.27, QED 0.37
Compound (SMILES): COc1ccc2nc3ccc(OC)cc3c(SCCCN)c2c1
InChIKey: ZFOMCSNUEHMROO-UHFFFAOYSA-N
Target: Dual specificity tyrosine-phosphorylation-regulated kinase 2 (SINGLE PROTEIN), Homo sapiens
UniProt: Q92630
Assay: Inhibition of recombinant human DYRK2 expressed in Sf9 insect cells incubated for 60 mins in presence of ATP and [gamma33-P] ATP by radiometric scintillation counter analysis
Measurement: IC50 = 17.5 nM (pChEMBL 7.760000228881836)
Descriptors: MW 328.44, ALogP 3.85, HBA 5, HBD 1, PSA 57.37, QED 0.42
Compound (SMILES): CC(C)C(=O)Nc1ncc(C(=O)NCCN(Cc2ccccc2)C(=O)c2ccc(S(=O)(=O)Nc3ccccc3)cc2)s1
InChIKey: YVPYJSSYGACUSE-UHFFFAOYSA-N
Target: LIM domain kinase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P53667
Assay: Inhibition of PAK mediated recombinant LIMK1 phosphorylation (330 to 637 residues) (unknown origin) incubated for 45 mins followed by ATP addition measured after 105 mins by RapidFire Mass Spectrometry kinase assay
Measurement: IC50 = 1.445 nM (pChEMBL 8.84000015258789)
Descriptors: MW 605.74, ALogP 4.61, HBA 7, HBD 3, PSA 137.57, QED 0.22
Compound (SMILES): C=CC(=O)Nc1cc(N2CCN(C)CC2)ccc1Nc1ncc2c(n1)-n1ccc(C(=O)Nc3c(CC)cccc3CC)c1CC2
InChIKey: QMTKZAHTDPRIFJ-UHFFFAOYSA-N
Target: Dual specificity protein kinase TTK (SINGLE PROTEIN), Homo sapiens
UniProt: P33981
Assay: Inhibition of recombinant human full length N-terminal GST-fused MPS1 (1 to 857 residues) using histone H3 as substrate by TR-FRET assay
Measurement: Ki = 0.83 nM (pChEMBL 9.079999923706055)
Descriptors: MW 604.76, ALogP 5.36, HBA 8, HBD 3, PSA 107.42, QED 0.22
Compound (SMILES): O=C(NCCCn1ccnc1)c1cc2nc(-c3ccccc3)cc(-c3ccccc3)n2n1
InChIKey: RIGHCDSORZCRDE-UHFFFAOYSA-N
Target: Alpha-2B adrenergic receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P18089
Assay: GPCRScan assay: inhibition of Alpha2B
Measurement: Ki = 3579.32 nM (pChEMBL 5.449999809265137)
Descriptors: MW 422.49, ALogP 4.08, HBA 6, HBD 1, PSA 77.11, QED 0.4
Compound (SMILES): CCNCCc1ccc(Cl)c(-c2ccccc2OC)c1.Cl
InChIKey: SXOXLJQRLIFVCQ-UHFFFAOYSA-N
Target: 5-hydroxytryptamine receptor 3A (SINGLE PROTEIN), Homo sapiens
UniProt: P46098
Assay: Binding affinity to 5-HT3R (unknown origin)
Measurement: Ki > 10000 nM (pChEMBL 5)
Descriptors: MW 289.81, ALogP 4.17, HBA 2, HBD 1, PSA 21.26, QED 0.81
Compound (SMILES): CCCN(CCC)CCc1ccc(Cl)c(-c2ccccc2OC)c1
InChIKey: IOJLDPRGTSPRBT-UHFFFAOYSA-N
Target: 5-hydroxytryptamine receptor 3A (SINGLE PROTEIN), Homo sapiens
UniProt: P46098
Assay: Binding affinity to 5-HT3R (unknown origin)
Measurement: Ki > 10000 nM (pChEMBL 5)
Descriptors: MW 345.91, ALogP 5.68, HBA 2, HBD 0, PSA 12.47, QED 0.58
Compound (SMILES): CCCCNCc1ccc(Cl)c(-c2ccccc2OC)c1
InChIKey: PKQCAZLGEGUDLP-UHFFFAOYSA-N
Target: 5-hydroxytryptamine receptor 6 (SINGLE PROTEIN), Homo sapiens
UniProt: P50406
Assay: Binding affinity to 5-HT6R (unknown origin)
Measurement: Ki = 240 nM (pChEMBL 6.619999885559082)
Descriptors: MW 303.83, ALogP 4.91, HBA 2, HBD 1, PSA 21.26, QED 0.73
Compound (SMILES): C[C@@H](c1cc(Cl)cc(Cl)c1)N1CCC(COc2cc(F)c(C(=O)NS(C)(=O)=O)cc2C2CC2)CC1
InChIKey: SXOAHIZWCZOILH-HNNXBMFYSA-N
Target: Sodium channel protein type 1 subunit alpha/beta-1/beta-2 (PROTEIN COMPLEX), Homo sapiens
UniProt: O60939
Assay: Inhibition of human Nav1.1/beta1/2 transfected in HEK293-A cells assessed as inhibition of channel current incubated for 5.5 mins by high-throughput electrophysiology system analysis
Measurement: IC50 = 202 nM (pChEMBL 6.699999809265137)
Descriptors: MW 543.49, ALogP 5.55, HBA 5, HBD 1, PSA 75.71, QED 0.47
Compound (SMILES): C[C@@H](COCCC(=O)N1CCN(c2ncc(C(F)(F)F)cn2)CC1)Nc1cn[nH]c(=O)c1C(F)(F)F
InChIKey: UQZCQKXJAXKZQH-LBPRGKRZSA-N
Target: Poly [ADP-ribose] polymerase 2 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9UGN5
Assay: Inhibition of N-terminal GST tagged human PARP2 (2 to 583 residues) infected in baculovirus infected Sf9 cells preincubated for 10 mins followed by PARP substrate addition and measured after 30 mins by fluorescence based analysis
Measurement: IC50 = 5.3 nM (pChEMBL 8.279999732971191)
Descriptors: MW 523.44, ALogP 2.15, HBA 8, HBD 2, PSA 116.34, QED 0.4
Compound (SMILES): CC(C)c1c2cc(-c3nc(Nc4ccc(N5CCNCC5)cn4)ncc3F)ccc2nn1C
InChIKey: LLFOBMRPWNABCB-UHFFFAOYSA-N
Target: CDK9/cyclin T1 (PROTEIN COMPLEX), Homo sapiens
UniProt: P50750
Assay: Inhibition of CDK9/cyclin T1 (unknown origin) in presence of 33P-gamma-ATP by scintillation counting method
Measurement: IC50 = 12.5 nM (pChEMBL 7.900000095367432)
Descriptors: MW 446.53, ALogP 3.84, HBA 8, HBD 2, PSA 83.79, QED 0.48
Compound (SMILES): C[C@H](CC[C@](C)(O)C(F)(F)F)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@](C)(O)CC[C@]4(C)[C@H]3CC[C@]12C
InChIKey: BVBRUQYHUXKZMQ-JNVAYQLDSA-N
Target: Voltage-gated potassium channel subunit Kv7.1/Misshapen-like kinase 1 (PROTEIN COMPLEX), Homo sapiens
UniProt: Q8N4C8
Assay: Inhibition of KCNQ1/MINK (unknown origin) by patch clamp method
Measurement: IC50 > 30000 nM (pChEMBL 4.5229997634887695)
Descriptors: MW 456.63, ALogP 7.05, HBA 2, HBD 2, PSA 40.46, QED 0.45
Compound (SMILES): CO[C@@H]1CCN(c2nccc(Nc3cc4c(C(C)C)ccc(N5C[C@H](CS(C)(=O)=O)[C@H]5C)c4cn3)n2)C[C@@H]1F
InChIKey: LIMFPAAAIVQRRD-BCGVJQADSA-N
Target: Epidermal growth factor receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P00533
Assay: Inhibition of wild type EGFR L858R/T790M/C797S triple mutant (unknown origin) phosphorylation expressed in mouse BaF3 cells by HTRF assay
Measurement: IC50 = 0.5 nM (pChEMBL 9.300000190734863)
Descriptors: MW 556.71, ALogP 4.32, HBA 9, HBD 1, PSA 100.55, QED 0.43
Compound (SMILES): COC[C@H](NC(=O)c1ccn(S(C)(=O)=O)c1)C(=O)Nc1nc(-c2cccc(N3C[C@@H](C)O[C@@H](C)C3)n2)cs1
InChIKey: JBLQNFBXKOAIHG-FCEWJHQRSA-N
Target: Cytochrome P450 3A4 (SINGLE PROTEIN), Homo sapiens
UniProt: P08684
Assay: Inhibition of CYP3A4 (unknown origin) using midazolam as testosterone
Measurement: IC50 = 22700 nM (pChEMBL 4.639999866485596)
Descriptors: MW 562.67, ALogP 1.81, HBA 11, HBD 2, PSA 144.75, QED 0.4
Compound (SMILES): Cc1nc(-c2cnc(NC(C)C)n(C)c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
InChIKey: TVGAHWWPABTBCX-UHFFFAOYSA-N
Target: Mast/stem cell growth factor receptor Kit (SINGLE PROTEIN), Homo sapiens
UniProt: P10721
Assay: Inhibition of KIT (unknown origin) in presence of 4 mM ATP measured by cell-based spectrophotometric assay
Measurement: IC50 = 1600 nM (pChEMBL 5.800000190734863)
Descriptors: MW 431.5, ALogP 3.56, HBA 9, HBD 1, PSA 99.75, QED 0.5
Compound (SMILES): C[C@@H](N)c1cc(Cl)ccc1Cn1c(=S)[nH]c(=O)c2[nH]ccc21
InChIKey: BHKKSKOHRFHHIN-MRVPVSSYSA-N
Target: Myeloperoxidase (SINGLE PROTEIN), Homo sapiens
UniProt: P05164
Assay: Inhibitory Activity: The pharmacological activity of compounds disclosed herein was tested in the following screen (Test A) in which the compounds were tested in the presence of ascorbate, which reacts with MPO-derived hypochlorous acid (HOCl) to form dehydro-ascorbate. The loss of ascorbate is followed by measuring absorbance at 260 nm.Assay buffer: 100 μM diethyl triamine pentaacetic acid (DTPA) in buffer consisting of 10 mM Na2HPO4/NaH2PO4, 3 mM KCl in 140 mM NaCl, pH 7.4.Enzyme solution: MPO purified from the human cell line HL60, 1.38 nM (final concentration 0.7 nM) and L-ascorbate, 100 μM (final concentration 50 μM) in Assay bufferSubstrate solution: H2O2, 98 μM (final concentration 49 μM) Forty μL of the enzyme solution was added to 0.6 μL compound serially diluted in DMSO. Absorbance was measured at 260 nm to obtain a compound blank value. After an additional 10 min, 40 μL of the substrate solution was added and the absorbance at 260 nm was recorded between 4 and 40 min to obtain kinetic readings of enzyme activity.
Measurement: IC50 = 7 nM (pChEMBL 8.149999618530273)
Descriptors: MW 334.83, ALogP 3.11, HBA 4, HBD 3, PSA 79.6, QED 0.64
Compound (SMILES): CCc1cc2ncc(CN3CCN(c4ccc(C(=O)NC)nc4)CC3)cc2[nH]c1=O
InChIKey: WQAVGRAETZEADU-UHFFFAOYSA-N
Target: Poly [ADP-ribose] polymerase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P09874
Assay: Inhibition of PARP1 (unknown origin) assessed as increase in DNA trapping activity measured after 60 mins by fluorescence anisotropy binding assay
Measurement: EC50 = 11.3 nM (pChEMBL 7.949999809265137)
Descriptors: MW 406.49, ALogP 1.56, HBA 6, HBD 2, PSA 94.22, QED 0.67
Compound (SMILES): CNC(=O)c1ccc(N2CCN(Cc3ccc4nc(C)c(=O)[nH]c4c3F)CC2)c(F)n1
InChIKey: WXRCLFFPZXJCLS-UHFFFAOYSA-N
Target: Poly [ADP-ribose] polymerase 2 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9UGN5
Assay: Inhibition of N-terminal GST-tagged human PARP2 (2 to 583 residues) expressed in baculovirus infected Sf9 cells assessed as increase in DNA trapping activity measured after 60 mins by fluorescence anisotropy binding assay
Measurement: EC50 = 7263 nM (pChEMBL 5.139999866485596)
Descriptors: MW 428.44, ALogP 1.59, HBA 6, HBD 2, PSA 94.22, QED 0.61
Compound (SMILES): NCCCC[C@H](NC(=O)C1CCCC1)C(=O)COc1c(F)ccc(F)c1F
InChIKey: OLIMBXKACVCIMM-HNNXBMFYSA-N
Target: Cathepsin L2 (SINGLE PROTEIN), Homo sapiens
UniProt: O60911
Assay: Inhibition of Lysine Gingipain: The capacities of compounds of the present invention to inhibit the activity of lysine gingipain were measured in a fluorogenic assay similar to those described by Barret (Biochemical Journal. 1980, 187(3), 909). The specific assay conditions were as follows. Buffer: pH=7.5, 100 mM Tris-HCl, 75 mM NaCl, 2.5 mM CaCl2), 10 mM cysteine, 1% DMSO after all additions. Protein: 0.1 nM Kgp, isolated from culture of Porphyromonas gingivalis, as described by Pike et al. (J. Biol. Chem. 1994, 269(1), 406), and Potempa and Nguyen (Current Protocols in Protein Science. 2007, 21.20.1-21.20.27). Fluorogenic substrate: 10 μM Z-His-Glu-Lys-MCA. Time=90 minutes. Temperature=37° C. Each compound: 10 concentrations, starting at either 100 μM or 100 nM, with lower concentrations generated by serial 3-fold dilutions. By testing a range of concentrations for each compound, the concentration required to inhibit the activity of lysine gingipain by 50% (the IC50) was determined. Under the described assay conditions, the signal-to-noise ratio was excellent, and the Z factor was greater than 0.6. Compounds in Table 1 were tested, as well as the compounds set forth in Table 2 below.The capacities of compounds of the present invention to inhibit the activity of cathepsins B, H, K, L, and S were measured in similar assays. Boc-Leu-Arg-Arg-AMC (20 μM) in sodium acetate buffer (50 mM, pH 5.5) containing DTT (1 mM) and EDTA (2 mM) was used for the Cathepsin B assay. L-Arg-AMC (20 μM) in sodium acetate buffer (50 mM, pH 5.5) containing DTT (1 mM) and EDTA (2 mM) was used for the Cathepsin H assay. Z-Phe-Arg-AMC (10 μM) in HEPES buffer (50 mM, pH 7.4) containing DTT (2.5 mM) and EDTA (1 mM) was used for the Cathepsin K assay. Z-Phe-Arg-AMC (20 μM) in sodium acetate buffer (50 mM, pH 5.5) containing DTT (1 mM) and EDTA (2 mM) was used for the Cathepsin L assay. Z-Leu-Arg-AMC (10 μM) in sodium acetate buffer (25 mM, pH 4.5) containing DTT (2.5 mM) and NaCl (50 mM) was used for the Cathepsin S assay.
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 386.41, ALogP 2.86, HBA 4, HBD 2, PSA 81.42, QED 0.48
Compound (SMILES): CC(=O)N1CCN([C@H]2CCC[C@@H](NC(=O)c3cc4c(F)ccc(C)c4[nH]3)C2)CC1
InChIKey: PGNLXEBQMQHFNK-SJORKVTESA-N
Target: Histone-lysine N-methyltransferase NSD2 (SINGLE PROTEIN), Homo sapiens
UniProt: O96028
Assay: Inhibition of MMSET (953 to 1240 residues) (unknown origin) by Alpha Screen assay
Measurement: IC50 = 18 nM (pChEMBL 7.75)
Descriptors: MW 400.5, ALogP 2.82, HBA 3, HBD 2, PSA 68.44, QED 0.83
Compound (SMILES): COCc1nn(Cc2ccc(Cn3ccccc3=O)cc2)cc1C(=O)NCc1nccc(OC)c1F
InChIKey: KGMPDQIYDKKXRD-UHFFFAOYSA-N
Target: Coagulation factor X (SINGLE PROTEIN), Homo sapiens
UniProt: P00742
Assay: Inhibition of human factor 10a preincubated for 5 mins followed by substrate addition by fluorometer analysis
Measurement: IC50 > 40000 nM (pChEMBL 4.3979997634887695)
Descriptors: MW 491.52, ALogP 2.76, HBA 8, HBD 1, PSA 100.27, QED 0.37
Compound (SMILES): COc1ccc2nc3ccc(OC)cc3c(SCCCN)c2c1
InChIKey: ZFOMCSNUEHMROO-UHFFFAOYSA-N
Target: Dual specificity tyrosine-phosphorylation-regulated kinase 3 (SINGLE PROTEIN), Homo sapiens
UniProt: O43781
Assay: Inhibition of recombinant human DYRK3 expressed in Sf9 insect cells incubated for 60 mins in presence of ATP and [gamma33-P] ATP by radiometric scintillation counter analysis
Measurement: IC50 = 223.1 nM (pChEMBL 6.650000095367432)
Descriptors: MW 328.44, ALogP 3.85, HBA 5, HBD 1, PSA 57.37, QED 0.42
Compound (SMILES): CC(C)C(=O)Nc1ncc(C(=O)NCCN(Cc2ccccc2)C(=O)c2ccc(S(=O)(=O)Nc3ccccc3)cc2)s1
InChIKey: YVPYJSSYGACUSE-UHFFFAOYSA-N
Target: LIM domain kinase 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P53671
Assay: Inhibition of PAK mediated recombinant LIMK2 phosphorylation (347 to 659 residues) (unknown origin) incubated for 45 mins followed by ATP addition measured after 180 mins by RapidFire Mass Spectrometry kinase assay
Measurement: IC50 = 7.079 nM (pChEMBL 8.149999618530273)
Descriptors: MW 605.74, ALogP 4.61, HBA 7, HBD 3, PSA 137.57, QED 0.22
Compound (SMILES): O=C(NCCCn1ccnc1)c1cc2nc(-c3ccccc3)cc(-c3ccccc3)n2n1
InChIKey: RIGHCDSORZCRDE-UHFFFAOYSA-N
Target: Alpha-2B adrenergic receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P18089
Assay: GPCRScan assay: inhibition of Alpha2B
Measurement: Ki = 3548.13 nM (pChEMBL 5.449999809265137)
Descriptors: MW 422.49, ALogP 4.08, HBA 6, HBD 1, PSA 77.11, QED 0.4
Compound (SMILES): CCNCCc1ccc(Cl)c(-c2ccccc2OC)c1.Cl
InChIKey: SXOXLJQRLIFVCQ-UHFFFAOYSA-N
Target: 5-hydroxytryptamine receptor 5A (SINGLE PROTEIN), Homo sapiens
UniProt: P47898
Assay: Binding affinity to 5-HT5AR (unknown origin)
Measurement: Ki = 700 nM (pChEMBL 6.159999847412109)
Descriptors: MW 289.81, ALogP 4.17, HBA 2, HBD 1, PSA 21.26, QED 0.81
Compound (SMILES): CCCN(CCC)CCc1ccc(Cl)c(-c2ccccc2OC)c1
InChIKey: IOJLDPRGTSPRBT-UHFFFAOYSA-N
Target: 5-hydroxytryptamine receptor 5A (SINGLE PROTEIN), Homo sapiens
UniProt: P47898
Assay: Binding affinity to 5-HT5AR (unknown origin)
Measurement: Ki = 2900 nM (pChEMBL 5.539999961853027)
Descriptors: MW 345.91, ALogP 5.68, HBA 2, HBD 0, PSA 12.47, QED 0.58
Compound (SMILES): C[C@@H](c1cc(Cl)cc(Cl)c1)N1CCC(COc2cc(F)c(C(=O)NS(C)(=O)=O)cc2C2CC2)CC1
InChIKey: SXOAHIZWCZOILH-HNNXBMFYSA-N
Target: Sodium channel protein type 5 subunit alpha/beta-1/beta-2 (PROTEIN COMPLEX), Homo sapiens
UniProt: O60939
Assay: Inhibition of human Nav1.5/beta1/2 transfected in HEK293-A cells assessed as inhibition of channel current incubated for 5.5 mins by high-throughput electrophysiology system analysis
Measurement: IC50 = 551 nM (pChEMBL 6.260000228881836)
Descriptors: MW 543.49, ALogP 5.55, HBA 5, HBD 1, PSA 75.71, QED 0.47
Compound (SMILES): C[C@@H](COCCC(=O)N1CCN(c2ncc(C(F)(F)F)cn2)CC1)Nc1cn[nH]c(=O)c1C(F)(F)F
InChIKey: UQZCQKXJAXKZQH-LBPRGKRZSA-N
Target: Poly [ADP-ribose] polymerase tankyrase-2 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9H2K2
Assay: Inhibition of N-terminal GST tagged human PARP5B (667 to 1166 residues) infected in baculovirus infected Sf9 cells preincubated for 10 mins followed by PARP substrate addition and measured after 30 mins by fluorescence based analysis
Measurement: IC50 > 5000 nM (pChEMBL 5.301000118255615)
Descriptors: MW 523.44, ALogP 2.15, HBA 8, HBD 2, PSA 116.34, QED 0.4
Compound (SMILES): CC(C)c1c2cc(-c3nc(Nc4ccc(N5CCNCC5)cn4)ncc3F)ccc2nn1C
InChIKey: LLFOBMRPWNABCB-UHFFFAOYSA-N
Target: Voltage-gated inwardly rectifying potassium channel KCNH2 (SINGLE PROTEIN), Homo sapiens
UniProt: Q12809
Assay: Inhibition of hERG
Measurement: IC50 = 5300 nM (pChEMBL 5.28000020980835)
Descriptors: MW 446.53, ALogP 3.84, HBA 8, HBD 2, PSA 83.79, QED 0.48
Compound (SMILES): C[C@H](CC[C@](C)(O)C(F)(F)F)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@](C)(O)CC[C@]4(C)[C@H]3CC[C@]12C
InChIKey: BVBRUQYHUXKZMQ-JNVAYQLDSA-N
Target: Voltage-dependent L-type calcium channel subunit alpha-1C (SINGLE PROTEIN), Homo sapiens
UniProt: Q13936
Assay: Inhibition of CaV1.2 (unknown origin) by patch clamp method
Measurement: IC50 > 30000 nM (pChEMBL 4.5229997634887695)
Descriptors: MW 456.63, ALogP 7.05, HBA 2, HBD 2, PSA 40.46, QED 0.45
Compound (SMILES): CO[C@@H]1CCN(c2nccc(Nc3cc4c(C(C)C)ccc(N5C[C@H](CS(C)(=O)=O)[C@H]5C)c4cn3)n2)C[C@@H]1F
InChIKey: LIMFPAAAIVQRRD-BCGVJQADSA-N
Target: Epidermal growth factor receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P00533
Assay: Inhibition of EGFR C797S/T790M/L858R mutant (unknown origin)
Measurement: IC50 = 0.2 nM (pChEMBL 9.699999809265137)
Descriptors: MW 556.71, ALogP 4.32, HBA 9, HBD 1, PSA 100.55, QED 0.43
Compound (SMILES): COC[C@H](NC(=O)c1ccn(S(C)(=O)=O)c1)C(=O)Nc1nc(-c2cccc(N3C[C@@H](C)O[C@@H](C)C3)n2)cs1
InChIKey: JBLQNFBXKOAIHG-FCEWJHQRSA-N
Target: Voltage-gated inwardly rectifying potassium channel KCNH2 (SINGLE PROTEIN), Homo sapiens
UniProt: Q12809
Assay: Inhibition of hERG expressed in CHO cells by manual patch clamp assay
Measurement: IC50 > 30000 nM (pChEMBL 4.5229997634887695)
Descriptors: MW 562.67, ALogP 1.81, HBA 11, HBD 2, PSA 144.75, QED 0.4
Compound (SMILES): Cc1nc(-c2cnc(NC(C)C)n(C)c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
InChIKey: TVGAHWWPABTBCX-UHFFFAOYSA-N
Target: Protein-tyrosine kinase 6 (SINGLE PROTEIN), Homo sapiens
UniProt: Q13882
Assay: Inhibition of BRK (unknown origin) in presence of 4 mM ATP measured by cell-based spectrophotometric assay
Measurement: IC50 = 2100 nM (pChEMBL 5.679999828338623)
Descriptors: MW 431.5, ALogP 3.56, HBA 9, HBD 1, PSA 99.75, QED 0.5
Compound (SMILES): C[C@@H](N)c1cc(Cl)ccc1Cn1c(=S)[nH]c(=O)c2[nH]ccc21
InChIKey: BHKKSKOHRFHHIN-MRVPVSSYSA-N
Target: Thyroid peroxidase (SINGLE PROTEIN), Homo sapiens
UniProt: P07202
Assay: Inhibitory Activity: To detect thyroid peroxidase (TPO) inhibitory activity, the production of hypoiodous acid (HOI) was quantified. HOI was detected by reacting it with methionine, which is converted to dehydro-methionine, which in turn is detected by reacting it with excess iodide at acidic pH. The reaction converts I− to I3 − that has absorbance at 353 nm. In brief, 0.6 μL compound serially diluted in DMSO was added to 25 μL 50 nM baculovirus-expressed recombinant human TPO (obtained from RSR Ltd, Cardiff, UK) in assay buffer (100 mM Na2HPO4/NaH2PO4, pH 7.4), after which absorbance at 353 nm was read to obtain a blank value. The enzyme reaction was initiated by the addition of 25 μL of a mix consisting of 2 mM methionine, 20 μM NaI and 100 μM H2O2 in assay buffer, and stopped by the addition of 10 μL catalase, 0.25 mg/mL. After an additional 5 min, 25 μL 600 mM sulphuric acid followed by 25 μL 100 mM KI were added, and absorbance at 353 nm was read 5 min after this addition. IC50 values of the compounds tested were obtained using standard procedures.In general, the compounds disclosed herein, which were tested, had a surprisingly high selectivity for the MPO enzyme over the TPO enzyme within the range of 220-1600 for the ratio IC50 (TPO)/IC50 (MPO).
Measurement: IC50 = 4300 nM (pChEMBL 5.369999885559082)
Descriptors: MW 334.83, ALogP 3.11, HBA 4, HBD 3, PSA 79.6, QED 0.64
Compound (SMILES): CCc1cc2ncc(CN3CCN(c4ccc(C(=O)NC)nc4)CC3)cc2[nH]c1=O
InChIKey: WQAVGRAETZEADU-UHFFFAOYSA-N
Target: Poly [ADP-ribose] polymerase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P09874
Assay: Inhibition of PARP1 (unknown origin) assessed as increase in DNA trapping activity measured after 120 mins by fluorescence anisotropy binding assay
Measurement: EC50 = 24.7 nM (pChEMBL 7.610000133514404)
Descriptors: MW 406.49, ALogP 1.56, HBA 6, HBD 2, PSA 94.22, QED 0.67
Compound (SMILES): NCCCC[C@H](NC(=O)C1CCCC1)C(=O)COc1c(F)ccc(F)c1F
InChIKey: OLIMBXKACVCIMM-HNNXBMFYSA-N
Target: Cathepsin S (SINGLE PROTEIN), Homo sapiens
UniProt: P25774
Assay: Inhibition of Lysine Gingipain: The capacities of compounds of the present invention to inhibit the activity of lysine gingipain were measured in a fluorogenic assay similar to those described by Barret (Biochemical Journal. 1980, 187(3), 909). The specific assay conditions were as follows. Buffer: pH=7.5, 100 mM Tris-HCl, 75 mM NaCl, 2.5 mM CaCl2), 10 mM cysteine, 1% DMSO after all additions. Protein: 0.1 nM Kgp, isolated from culture of Porphyromonas gingivalis, as described by Pike et al. (J. Biol. Chem. 1994, 269(1), 406), and Potempa and Nguyen (Current Protocols in Protein Science. 2007, 21.20.1-21.20.27). Fluorogenic substrate: 10 μM Z-His-Glu-Lys-MCA. Time=90 minutes. Temperature=37° C. Each compound: 10 concentrations, starting at either 100 μM or 100 nM, with lower concentrations generated by serial 3-fold dilutions. By testing a range of concentrations for each compound, the concentration required to inhibit the activity of lysine gingipain by 50% (the IC50) was determined. Under the described assay conditions, the signal-to-noise ratio was excellent, and the Z factor was greater than 0.6. Compounds in Table 1 were tested, as well as the compounds set forth in Table 2 below.The capacities of compounds of the present invention to inhibit the activity of cathepsins B, H, K, L, and S were measured in similar assays. Boc-Leu-Arg-Arg-AMC (20 μM) in sodium acetate buffer (50 mM, pH 5.5) containing DTT (1 mM) and EDTA (2 mM) was used for the Cathepsin B assay. L-Arg-AMC (20 μM) in sodium acetate buffer (50 mM, pH 5.5) containing DTT (1 mM) and EDTA (2 mM) was used for the Cathepsin H assay. Z-Phe-Arg-AMC (10 μM) in HEPES buffer (50 mM, pH 7.4) containing DTT (2.5 mM) and EDTA (1 mM) was used for the Cathepsin K assay. Z-Phe-Arg-AMC (20 μM) in sodium acetate buffer (50 mM, pH 5.5) containing DTT (1 mM) and EDTA (2 mM) was used for the Cathepsin L assay. Z-Leu-Arg-AMC (10 μM) in sodium acetate buffer (25 mM, pH 4.5) containing DTT (2.5 mM) and NaCl (50 mM) was used for the Cathepsin S assay.
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 386.41, ALogP 2.86, HBA 4, HBD 2, PSA 81.42, QED 0.48
Compound (SMILES): COCc1nn(Cc2ccc(Cn3ccccc3=O)cc2)cc1C(=O)NCc1nccc(OC)c1F
InChIKey: KGMPDQIYDKKXRD-UHFFFAOYSA-N
Target: Coagulation factor VII (SINGLE PROTEIN), Homo sapiens
UniProt: P08709
Assay: Inhibition of human factor 7a preincubated for 5 mins followed by substrate addition by fluorometer analysis
Measurement: IC50 > 40000 nM (pChEMBL 4.3979997634887695)
Descriptors: MW 491.52, ALogP 2.76, HBA 8, HBD 1, PSA 100.27, QED 0.37
Compound (SMILES): COc1ccc2nc3ccc(OC)cc3c(SCCCN)c2c1
InChIKey: ZFOMCSNUEHMROO-UHFFFAOYSA-N
Target: Dual specificity tyrosine-phosphorylation-regulated kinase 4 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9NR20
Assay: Inhibition of recombinant human DYRK4 expressed in Sf9 insect cells incubated for 60 mins in presence of ATP and [gamma33-P] ATP by radiometric scintillation counter analysis
Measurement: IC50 = 584.2 nM (pChEMBL 6.230000019073486)
Descriptors: MW 328.44, ALogP 3.85, HBA 5, HBD 1, PSA 57.37, QED 0.42
Compound (SMILES): CC(C)C(=O)Nc1ncc(C(=O)NCCN(Cc2ccccc2)C(=O)c2ccc(S(=O)(=O)Nc3ccccc3)cc2)s1
InChIKey: YVPYJSSYGACUSE-UHFFFAOYSA-N
Target: LIM domain kinase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P53667
Assay: Inhibition of recombinant LIMK1(unknown origin) expressed in HEK293 cells using NanoGlo substrate incubated for 2 hrs followed by substrate addition by NanoBRET assay
Measurement: IC50 = 25.7 nM (pChEMBL 7.590000152587891)
Descriptors: MW 605.74, ALogP 4.61, HBA 7, HBD 3, PSA 137.57, QED 0.22
Compound (SMILES): O=C(NCCCn1ccnc1)c1cc2nc(-c3ccccc3)cc(-c3ccccc3)n2n1
InChIKey: RIGHCDSORZCRDE-UHFFFAOYSA-N
Target: Kappa-type opioid receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P41145
Assay: GPCRScan assay: inhibition of KOR
Measurement: Ki = 1168.96 nM (pChEMBL 5.929999828338623)
Descriptors: MW 422.49, ALogP 4.08, HBA 6, HBD 1, PSA 77.11, QED 0.4
Compound (SMILES): CCNCCc1ccc(Cl)c(-c2ccccc2OC)c1.Cl
InChIKey: SXOXLJQRLIFVCQ-UHFFFAOYSA-N
Target: 5-hydroxytryptamine receptor 6 (SINGLE PROTEIN), Homo sapiens
UniProt: P50406
Assay: Binding affinity to 5-HT6R (unknown origin)
Measurement: Ki > 10000 nM (pChEMBL 5)
Descriptors: MW 289.81, ALogP 4.17, HBA 2, HBD 1, PSA 21.26, QED 0.81
Compound (SMILES): CCCN(CCC)CCc1ccc(Cl)c(-c2ccccc2OC)c1
InChIKey: IOJLDPRGTSPRBT-UHFFFAOYSA-N
Target: 5-hydroxytryptamine receptor 6 (SINGLE PROTEIN), Homo sapiens
UniProt: P50406
Assay: Binding affinity to 5-HT6R (unknown origin)
Measurement: Ki > 10000 nM (pChEMBL 5)
Descriptors: MW 345.91, ALogP 5.68, HBA 2, HBD 0, PSA 12.47, QED 0.58
Compound (SMILES): C[C@@H](c1cc(Cl)cc(Cl)c1)N1CCC(COc2cc(F)c(C(=O)NS(C)(=O)=O)cc2C2CC2)CC1
InChIKey: SXOAHIZWCZOILH-HNNXBMFYSA-N
Target: Sodium channel protein type 9 subunit alpha (SINGLE PROTEIN), Homo sapiens
UniProt: Q15858
Assay: Electrophysiological Assay (EP) (In vitro Assay): Patch voltage clamp electrophysiology allows for the direct measurement and quantification of block of voltage-gated sodium channels (NaV's), and allows the determination of the time- and voltage-dependence of block which has been interpreted as differential binding to the resting, open, and inactivated states of the sodium channel (Hille, B., Journal of General Physiology (1977), 69: 497-515).The following patch voltage clamp electrophysiology studies were performed on representative compounds of the invention using human embryonic kidney cells (HEK), permanently transfected with an expression vector containing the full-length cDNA coding for the desired human sodium channel α-subunit, grown in culture media containing 10% FBS, 1% PSG, and 0.5 mg/mL G418 at 37° C. with 5% CO2. HEK cells used for the electrophysiology (EP) recordings had a passage number of less than 40 for all studies and were used within three days from the time of plating, NaV1.7 and NaV1.5 cDNAs (NM_002977 and AC137587; SCN5A, respectively) were stably expressed in HEK-293 cells. The β1 subunit was coexpressed in both the NaV1.7 and NaV1.5 cell lines.Sodium currents were measured rising the patch clamp technique in the whole-cell configuration using either a PatchXpress automated voltage clamp or manually using an Axopatch 200B (Axon Instruments) or Model 2400 (A-M systems) amplifier. The manual voltage clamp protocol was as follows: Borosilicate glass micropipettes were fire-polished to a tip diameter yielding a resistance of 2-4 Mohms in the working solutions. The pipette was filled with a solution comprised of: 5 mM NaCl, 10 mM CsCl, 120 mM CsF, 0.1 mM CaCl2, 2 mM MgCl2, 10 mM HEPES, 10 mM EGTA; and adjusted to pH 7.2 with CsOH. The external solution had the following composition: 140 mM NaCl, 5 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 10 mM HEPES; and adjusted to pH 7.4 with NaOH. In some studies, the external sodium was reduced by equimolar replacement with choline. Osmolality in the CsF internal and NaCl external solutions was adjusted to 300 mOsm/kg and 310 mOsm/kg with glucose, respectively. All recordings were performed at ambient temperature in a bath chamber with a volume of 150 μL. Control sodium currents were measured in 0.5% DMSO.
Measurement: IC50 = 5.8 nM (pChEMBL 8.239999771118164)
Descriptors: MW 543.49, ALogP 5.55, HBA 5, HBD 1, PSA 75.71, QED 0.47
Compound (SMILES): C[C@@H](COCCC(=O)N1CCN(c2ncc(C(F)(F)F)cn2)CC1)Nc1cn[nH]c(=O)c1C(F)(F)F
InChIKey: UQZCQKXJAXKZQH-LBPRGKRZSA-N
Target: Poly [ADP-ribose] polymerase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P09874
Assay: Inhibition of PARP1 (unknown origin)
Measurement: IC50 = 34 nM (pChEMBL 7.46999979019165)
Descriptors: MW 523.44, ALogP 2.15, HBA 8, HBD 2, PSA 116.34, QED 0.4
Compound (SMILES): Cc1n[nH]c(C)c1-c1cnn(C2(CC#N)CN(c3cc(F)c(C(=O)N[C@@H](C)C(F)(F)F)cc3F)C2)c1
InChIKey: MSGYSFWCPOBHEV-AWEZNQCLSA-N
Target: Tyrosine-protein kinase JAK1 (SINGLE PROTEIN), Homo sapiens
UniProt: P23458
Assay: Enzyme Assay: The kinase reaction was conducted in clear-bottom 96-well plate from Thermo Fisher Scientific in a final volume of 24 μL. Inhibitors were first diluted serially in DMSO and added to the plate wells before the addition of other reaction components. The final concentration of DMSO in the assay was 0.5%. The PI3K assays were carried out at room temperature in 20 mM MOPS, pH 6.7, 10 mM MgCl2, 5 mM DTT and CHAPS 0.03%. The reaction mixture was prepared containing 50 μM PIP2, kinase and varying concentration of inhibitors. Reactions were initiated by the addition of ATP containing 2.2 μCi [γ-33P]ATP to a final concentration of 1000 μM. The final concentration of PI3K isoforms α, β, δ and γ in the assay were 1.3, 9.4, 2.9 and 10.8 nM respectively. Reactions were incubated for 180 min and terminated by the addition of 100 μL of 1 M potassium phosphate pH 8.0, 30 mM EDTA quench buffer. A 100 μL aliquot of the reaction solution was then transferred to 96-well Millipore MultiScreen IP 0.45 μm PVDF filter plate (The filter plate was prewetted with 200 μL 100% ethanol, distilled water, and 1 M potassium phosphate pH 8.0, respectively). The filter plate was aspirated on a Millipore Manifold under vacuum and washed with 18×200 μL wash buffer containing 1 M potassium phosphate pH 8.0 and 1 mM ATP. After drying by aspiration and blotting, the plate was air dried in an incubator at 37° C. overnight. Packard TopCount adapter (Millipore) was then attached to the plate followed with addition of 120 μL Microscint 20 scintillation cocktail (Perkin Elmer) in each well. After the plate sealing, the radioactivity of the product was determined by scintillation counting on Topcount (Perkin-Elmer).
Measurement: IC50 < 300 nM (pChEMBL 6.5229997634887695)
Descriptors: MW 507.47, ALogP 3.98, HBA 6, HBD 2, PSA 102.63, QED 0.49
Compound (SMILES): CC(C)c1c2cc(-c3nc(Nc4ccc(N5CCNCC5)cn4)ncc3F)ccc2nn1C
InChIKey: LLFOBMRPWNABCB-UHFFFAOYSA-N
Target: Cytochrome P450 3A4 (SINGLE PROTEIN), Homo sapiens
UniProt: P08684
Assay: Inhibition of CYP3A4 (unknown origin) using midazolam as substrate
Measurement: IC50 > 50000 nM (pChEMBL 4.301000118255615)
Descriptors: MW 446.53, ALogP 3.84, HBA 8, HBD 2, PSA 83.79, QED 0.48
Compound (SMILES): C[C@H](CC[C@](C)(O)C(F)(F)F)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@](C)(O)CC[C@]4(C)[C@H]3CC[C@]12C
InChIKey: BVBRUQYHUXKZMQ-JNVAYQLDSA-N
Target: Potassium voltage-gated channel subfamily A member 5 (SINGLE PROTEIN), Homo sapiens
UniProt: P22460
Assay: Inhibition of Kv1.5 (unknown origin) by patch clamp method
Measurement: IC50 > 30000 nM (pChEMBL 4.5229997634887695)
Descriptors: MW 456.63, ALogP 7.05, HBA 2, HBD 2, PSA 40.46, QED 0.45
Compound (SMILES): Cc1nc(-c2cnc(NC(C)C)n(C)c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
InChIKey: TVGAHWWPABTBCX-UHFFFAOYSA-N
Target: Tyrosine-protein kinase Lck (SINGLE PROTEIN), Homo sapiens
UniProt: P06239
Assay: Inhibition of LCK (unknown origin) in presence of 4 mM ATP measured by cell-based spectrophotometric assay
Measurement: IC50 = 2800 nM (pChEMBL 5.550000190734863)
Descriptors: MW 431.5, ALogP 3.56, HBA 9, HBD 1, PSA 99.75, QED 0.5
Compound (SMILES): CCc1cc2ncc(CN3CCN(c4ccc(C(=O)NC)nc4)CC3)cc2[nH]c1=O
InChIKey: WQAVGRAETZEADU-UHFFFAOYSA-N
Target: Poly [ADP-ribose] polymerase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P09874
Assay: Inhibition of PARP1 (unknown origin) assessed as increase in DNA trapping activity measured after 180 mins by fluorescence anisotropy binding assay
Measurement: EC50 = 36 nM (pChEMBL 7.440000057220459)
Descriptors: MW 406.49, ALogP 1.56, HBA 6, HBD 2, PSA 94.22, QED 0.67
Compound (SMILES): NCCCC[C@H](NC(=O)C1CCCC1)C(=O)COc1c(F)ccc(F)c1F
InChIKey: OLIMBXKACVCIMM-HNNXBMFYSA-N
Target: Cathepsin Z (SINGLE PROTEIN), Homo sapiens
UniProt: Q9UBR2
Assay: Inhibition of Lysine Gingipain: The capacities of compounds of the present invention to inhibit the activity of lysine gingipain were measured in a fluorogenic assay similar to those described by Barret (Biochemical Journal. 1980, 187(3), 909). The specific assay conditions were as follows. Buffer: pH=7.5, 100 mM Tris-HCl, 75 mM NaCl, 2.5 mM CaCl2), 10 mM cysteine, 1% DMSO after all additions. Protein: 0.1 nM Kgp, isolated from culture of Porphyromonas gingivalis, as described by Pike et al. (J. Biol. Chem. 1994, 269(1), 406), and Potempa and Nguyen (Current Protocols in Protein Science. 2007, 21.20.1-21.20.27). Fluorogenic substrate: 10 μM Z-His-Glu-Lys-MCA. Time=90 minutes. Temperature=37° C. Each compound: 10 concentrations, starting at either 100 μM or 100 nM, with lower concentrations generated by serial 3-fold dilutions. By testing a range of concentrations for each compound, the concentration required to inhibit the activity of lysine gingipain by 50% (the IC50) was determined. Under the described assay conditions, the signal-to-noise ratio was excellent, and the Z factor was greater than 0.6. Compounds in Table 1 were tested, as well as the compounds set forth in Table 2 below.The capacities of compounds of the present invention to inhibit the activity of cathepsins B, H, K, L, and S were measured in similar assays. Boc-Leu-Arg-Arg-AMC (20 μM) in sodium acetate buffer (50 mM, pH 5.5) containing DTT (1 mM) and EDTA (2 mM) was used for the Cathepsin B assay. L-Arg-AMC (20 μM) in sodium acetate buffer (50 mM, pH 5.5) containing DTT (1 mM) and EDTA (2 mM) was used for the Cathepsin H assay. Z-Phe-Arg-AMC (10 μM) in HEPES buffer (50 mM, pH 7.4) containing DTT (2.5 mM) and EDTA (1 mM) was used for the Cathepsin K assay. Z-Phe-Arg-AMC (20 μM) in sodium acetate buffer (50 mM, pH 5.5) containing DTT (1 mM) and EDTA (2 mM) was used for the Cathepsin L assay. Z-Leu-Arg-AMC (10 μM) in sodium acetate buffer (25 mM, pH 4.5) containing DTT (2.5 mM) and NaCl (50 mM) was used for the Cathepsin S assay.
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 386.41, ALogP 2.86, HBA 4, HBD 2, PSA 81.42, QED 0.48
Compound (SMILES): COCc1nn(Cc2ccc(Cn3ccccc3=O)cc2)cc1C(=O)NCc1nccc(OC)c1F
InChIKey: KGMPDQIYDKKXRD-UHFFFAOYSA-N
Target: Plasminogen (SINGLE PROTEIN), Homo sapiens
UniProt: P00747
Assay: Inhibition of human plasmin preincubated for 5 mins followed by substrate addition by fluorometer analysis
Measurement: IC50 > 40000 nM (pChEMBL 4.3979997634887695)
Descriptors: MW 491.52, ALogP 2.76, HBA 8, HBD 1, PSA 100.27, QED 0.37
Compound (SMILES): COc1ccc2nc3ccc(OC)cc3c(SCCCN)c2c1
InChIKey: ZFOMCSNUEHMROO-UHFFFAOYSA-N
Target: Glycogen synthase kinase-3 beta (SINGLE PROTEIN), Homo sapiens
UniProt: P49841
Assay: Inhibition of recombinant human GSK-3beta expressed in Sf9 insect cells incubated for 60 mins in presence of ATP and [gamma33-P] ATP by radiometric scintillation counter analysis
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 328.44, ALogP 3.85, HBA 5, HBD 1, PSA 57.37, QED 0.42
Compound (SMILES): CC(C)C(=O)Nc1ncc(C(=O)NCCN(Cc2ccccc2)C(=O)c2ccc(S(=O)(=O)Nc3ccccc3)cc2)s1
InChIKey: YVPYJSSYGACUSE-UHFFFAOYSA-N
Target: LIM domain kinase 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P53671
Assay: Inhibition of recombinant LIMK2(unknown origin) expressed in HEK293 cells using NanoGlo substrate incubated for 2 hrs followed by substrate addition by NanoBRET assay
Measurement: IC50 = 26.92 nM (pChEMBL 7.570000171661377)
Descriptors: MW 605.74, ALogP 4.61, HBA 7, HBD 3, PSA 137.57, QED 0.22
Compound (SMILES): O=C(NCCCn1ccnc1)c1cc2nc(-c3ccccc3)cc(-c3ccccc3)n2n1
InChIKey: RIGHCDSORZCRDE-UHFFFAOYSA-N
Target: Kappa-type opioid receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P41145
Assay: GPCRScan assay: inhibition of KOR
Measurement: Ki = 1174.9 nM (pChEMBL 5.929999828338623)
Descriptors: MW 422.49, ALogP 4.08, HBA 6, HBD 1, PSA 77.11, QED 0.4
Compound (SMILES): C[C@@H](COCCC(=O)N1CCN(c2ncc(C(F)(F)F)cn2)CC1)Nc1cn[nH]c(=O)c1C(F)(F)F
InChIKey: UQZCQKXJAXKZQH-LBPRGKRZSA-N
Target: Protein mono-ADP-ribosyltransferase TIPARP (SINGLE PROTEIN), Homo sapiens
UniProt: Q7Z3E1
Assay: Inhibition of PARP7 (unknown origin) measured after 1 hr incubation by microplate reader assay
Measurement: IC50 = 5.6 nM (pChEMBL 8.25)
Descriptors: MW 523.44, ALogP 2.15, HBA 8, HBD 2, PSA 116.34, QED 0.4