lovingscience/chembl-v37-raw-activities huggingface dataset:
Compound (SMILES): CCc1ncnc(-c2ccc(C(=O)N3CC[C@H](O)C3)c(Cl)c2)c1C#Cc1ccc(N)nc1
InChIKey: LAIACFMZANZCBH-KRWDZBQOSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42336
Assay: Filter-Binding-Assay: PI3Kalpha assay described herein provides IC50 values indicating the activity of the compounds inhibiting PI3 kinase alpha activity Inhibition of PI3 kinase is expected to be indicative of activity in treating conditions of excessive or anomalous cell proliferation, such as cancers. See also J. A. Engelman, Nature Reviews Cancer, 2009, 9, 550-562; A. Carnero, Expert Opin. Investig. Drugs, 2009, 18, 1265-1277 and P. Liu et al., Nature Reviews Drug Discovery, 2009, 8, 627-64.
Measurement: IC50 = 58 nM (pChEMBL 7.239999771118164)
Descriptors: MW 447.93, ALogP 2.94, HBA 6, HBD 2, PSA 105.23, QED 0.6
Compound (SMILES): CCc1ncnc(-c2ccc(C(=O)N3CC[C@@H](O)C3)c(Cl)c2)c1C#Cc1ccc(N)nc1
InChIKey: LAIACFMZANZCBH-QGZVFWFLSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42336
Assay: Filter-Binding-Assay: PI3Kalpha assay described herein provides IC50 values indicating the activity of the compounds inhibiting PI3 kinase alpha activity Inhibition of PI3 kinase is expected to be indicative of activity in treating conditions of excessive or anomalous cell proliferation, such as cancers. See also J. A. Engelman, Nature Reviews Cancer, 2009, 9, 550-562; A. Carnero, Expert Opin. Investig. Drugs, 2009, 18, 1265-1277 and P. Liu et al., Nature Reviews Drug Discovery, 2009, 8, 627-64.
Measurement: IC50 = 66 nM (pChEMBL 7.179999828338623)
Descriptors: MW 447.93, ALogP 2.94, HBA 6, HBD 2, PSA 105.23, QED 0.6
Compound (SMILES): CCc1ncnc(-c2ccc(C(=O)N3CCCC(O)C3)c(Cl)c2)c1C#Cc1ccc(N)nc1
InChIKey: UBGHRKJLOVCWTO-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42336
Assay: Filter-Binding-Assay: PI3Kalpha assay described herein provides IC50 values indicating the activity of the compounds inhibiting PI3 kinase alpha activity Inhibition of PI3 kinase is expected to be indicative of activity in treating conditions of excessive or anomalous cell proliferation, such as cancers. See also J. A. Engelman, Nature Reviews Cancer, 2009, 9, 550-562; A. Carnero, Expert Opin. Investig. Drugs, 2009, 18, 1265-1277 and P. Liu et al., Nature Reviews Drug Discovery, 2009, 8, 627-64.
Measurement: IC50 = 65 nM (pChEMBL 7.190000057220459)
Descriptors: MW 461.95, ALogP 3.33, HBA 6, HBD 2, PSA 105.23, QED 0.58
Compound (SMILES): CCc1ncnc(-c2ccc(C(=O)N3CCC(N4CCCCCC4)CC3)c(Cl)c2)c1C#Cc1ccc(N)nc1
InChIKey: LFIRBBMGSZJGOD-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42336
Assay: Filter-Binding-Assay: PI3Kalpha assay described herein provides IC50 values indicating the activity of the compounds inhibiting PI3 kinase alpha activity Inhibition of PI3 kinase is expected to be indicative of activity in treating conditions of excessive or anomalous cell proliferation, such as cancers. See also J. A. Engelman, Nature Reviews Cancer, 2009, 9, 550-562; A. Carnero, Expert Opin. Investig. Drugs, 2009, 18, 1265-1277 and P. Liu et al., Nature Reviews Drug Discovery, 2009, 8, 627-64.
Measurement: IC50 = 420 nM (pChEMBL 6.380000114440918)
Descriptors: MW 543.12, ALogP 5.22, HBA 6, HBD 1, PSA 88.24, QED 0.45
Compound (SMILES): CCc1ncnc(-c2ccc(C(=O)N3CCC(N(C)C)CC3)c(Cl)c2)c1C#Cc1ccc(N)nc1
InChIKey: RDIUCBRUWWJBNS-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42336
Assay: Filter-Binding-Assay: PI3Kalpha assay described herein provides IC50 values indicating the activity of the compounds inhibiting PI3 kinase alpha activity Inhibition of PI3 kinase is expected to be indicative of activity in treating conditions of excessive or anomalous cell proliferation, such as cancers. See also J. A. Engelman, Nature Reviews Cancer, 2009, 9, 550-562; A. Carnero, Expert Opin. Investig. Drugs, 2009, 18, 1265-1277 and P. Liu et al., Nature Reviews Drug Discovery, 2009, 8, 627-64.
Measurement: IC50 = 433 nM (pChEMBL 6.360000133514404)
Descriptors: MW 489.02, ALogP 3.9, HBA 6, HBD 1, PSA 88.24, QED 0.56
Compound (SMILES): CCc1ncnc(-c2ccc(C(=O)N3CCC(N(C)C)C3)c(Cl)c2)c1C#Cc1ccc(N)nc1
InChIKey: ZSTKPVNMFBRRQO-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42336
Assay: Filter-Binding-Assay: PI3Kalpha assay described herein provides IC50 values indicating the activity of the compounds inhibiting PI3 kinase alpha activity Inhibition of PI3 kinase is expected to be indicative of activity in treating conditions of excessive or anomalous cell proliferation, such as cancers. See also J. A. Engelman, Nature Reviews Cancer, 2009, 9, 550-562; A. Carnero, Expert Opin. Investig. Drugs, 2009, 18, 1265-1277 and P. Liu et al., Nature Reviews Drug Discovery, 2009, 8, 627-64.
Measurement: IC50 = 177 nM (pChEMBL 6.75)
Descriptors: MW 475, ALogP 3.51, HBA 6, HBD 1, PSA 88.24, QED 0.58
Compound (SMILES): CCc1ncnc(-c2ccc(C(=O)N3CCC(N4CCCC4)CC3)c(Cl)c2)c1C#Cc1ccc(N)nc1
InChIKey: ROQKQUMSXPXEQY-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42336
Assay: Filter-Binding-Assay: PI3Kalpha assay described herein provides IC50 values indicating the activity of the compounds inhibiting PI3 kinase alpha activity Inhibition of PI3 kinase is expected to be indicative of activity in treating conditions of excessive or anomalous cell proliferation, such as cancers. See also J. A. Engelman, Nature Reviews Cancer, 2009, 9, 550-562; A. Carnero, Expert Opin. Investig. Drugs, 2009, 18, 1265-1277 and P. Liu et al., Nature Reviews Drug Discovery, 2009, 8, 627-64.
Measurement: IC50 = 467 nM (pChEMBL 6.329999923706055)
Descriptors: MW 515.06, ALogP 4.44, HBA 6, HBD 1, PSA 88.24, QED 0.52
Compound (SMILES): CCc1ncnc(-c2ccc(C(=O)N3CCNCC3)c(Cl)c2)c1C#Cc1ccc(N)nc1
InChIKey: BXOVUYYOEDDRHM-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42336
Assay: Filter-Binding-Assay: PI3Kalpha assay described herein provides IC50 values indicating the activity of the compounds inhibiting PI3 kinase alpha activity Inhibition of PI3 kinase is expected to be indicative of activity in treating conditions of excessive or anomalous cell proliferation, such as cancers. See also J. A. Engelman, Nature Reviews Cancer, 2009, 9, 550-562; A. Carnero, Expert Opin. Investig. Drugs, 2009, 18, 1265-1277 and P. Liu et al., Nature Reviews Drug Discovery, 2009, 8, 627-64.
Measurement: IC50 = 164 nM (pChEMBL 6.789999961853027)
Descriptors: MW 446.94, ALogP 2.78, HBA 6, HBD 2, PSA 97.03, QED 0.6
Compound (SMILES): CCc1ncnc(-c2ccc(C(=O)N(C)O)c(Cl)c2)c1C#Cc1ccc(N)nc1
InChIKey: HBATYDBTFKDWAU-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42336
Assay: Filter-Binding-Assay: PI3Kalpha assay described herein provides IC50 values indicating the activity of the compounds inhibiting PI3 kinase alpha activity Inhibition of PI3 kinase is expected to be indicative of activity in treating conditions of excessive or anomalous cell proliferation, such as cancers. See also J. A. Engelman, Nature Reviews Cancer, 2009, 9, 550-562; A. Carnero, Expert Opin. Investig. Drugs, 2009, 18, 1265-1277 and P. Liu et al., Nature Reviews Drug Discovery, 2009, 8, 627-64.
Measurement: IC50 = 67 nM (pChEMBL 7.170000076293945)
Descriptors: MW 407.86, ALogP 3.2, HBA 6, HBD 2, PSA 105.23, QED 0.39
Compound (SMILES): CCc1ncnc(-c2ccc(C(=O)N3CCCN(C)CC3)c(Cl)c2)c1C#Cc1ccc(N)nc1
InChIKey: MJTBKQARMIXXSB-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42336
Assay: Filter-Binding-Assay: PI3Kalpha assay described herein provides IC50 values indicating the activity of the compounds inhibiting PI3 kinase alpha activity Inhibition of PI3 kinase is expected to be indicative of activity in treating conditions of excessive or anomalous cell proliferation, such as cancers. See also J. A. Engelman, Nature Reviews Cancer, 2009, 9, 550-562; A. Carnero, Expert Opin. Investig. Drugs, 2009, 18, 1265-1277 and P. Liu et al., Nature Reviews Drug Discovery, 2009, 8, 627-64.
Measurement: IC50 = 405 nM (pChEMBL 6.389999866485596)
Descriptors: MW 475, ALogP 3.51, HBA 6, HBD 1, PSA 88.24, QED 0.58
Compound (SMILES): CCc1ncnc(-c2ccc(C(=O)N3CCN(c4ccncc4)CC3)c(Cl)c2)c1C#Cc1ccc(N)nc1
InChIKey: WKGQOTMGNCYXIJ-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42336
Assay: Filter-Binding-Assay: PI3Kalpha assay described herein provides IC50 values indicating the activity of the compounds inhibiting PI3 kinase alpha activity Inhibition of PI3 kinase is expected to be indicative of activity in treating conditions of excessive or anomalous cell proliferation, such as cancers. See also J. A. Engelman, Nature Reviews Cancer, 2009, 9, 550-562; A. Carnero, Expert Opin. Investig. Drugs, 2009, 18, 1265-1277 and P. Liu et al., Nature Reviews Drug Discovery, 2009, 8, 627-64.
Measurement: IC50 = 209 nM (pChEMBL 6.679999828338623)
Descriptors: MW 524.03, ALogP 4.09, HBA 7, HBD 1, PSA 101.13, QED 0.4
Compound (SMILES): CCc1ncnc(-c2ccc(C(=O)N3CCCOCC3)c(Cl)c2)c1C#Cc1ccc(N)nc1
InChIKey: QSZHQEONAFXDOB-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42336
Assay: Filter-Binding-Assay: PI3Kalpha assay described herein provides IC50 values indicating the activity of the compounds inhibiting PI3 kinase alpha activity Inhibition of PI3 kinase is expected to be indicative of activity in treating conditions of excessive or anomalous cell proliferation, such as cancers. See also J. A. Engelman, Nature Reviews Cancer, 2009, 9, 550-562; A. Carnero, Expert Opin. Investig. Drugs, 2009, 18, 1265-1277 and P. Liu et al., Nature Reviews Drug Discovery, 2009, 8, 627-64.
Measurement: IC50 = 65 nM (pChEMBL 7.190000057220459)
Descriptors: MW 461.95, ALogP 3.6, HBA 6, HBD 1, PSA 94.23, QED 0.6
Compound (SMILES): CCc1ncnc(-c2ccc(C(=O)NCC3(C)COC3)c(Cl)c2)c1C#Cc1ccc(N)nc1
InChIKey: ACRVFUXUPCCBKG-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42336
Assay: Filter-Binding-Assay: PI3Kalpha assay described herein provides IC50 values indicating the activity of the compounds inhibiting PI3 kinase alpha activity Inhibition of PI3 kinase is expected to be indicative of activity in treating conditions of excessive or anomalous cell proliferation, such as cancers. See also J. A. Engelman, Nature Reviews Cancer, 2009, 9, 550-562; A. Carnero, Expert Opin. Investig. Drugs, 2009, 18, 1265-1277 and P. Liu et al., Nature Reviews Drug Discovery, 2009, 8, 627-64.
Measurement: IC50 = 66 nM (pChEMBL 7.179999828338623)
Descriptors: MW 461.95, ALogP 3.5, HBA 6, HBD 2, PSA 103.02, QED 0.56
Compound (SMILES): CCc1ncnc(-c2ccc(C(=O)N3CCN(Cc4ccccc4)CC3)c(Cl)c2)c1C#Cc1ccc(N)nc1
InChIKey: NGSVBOQNKNOEJK-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42336
Assay: Filter-Binding-Assay: PI3Kalpha assay described herein provides IC50 values indicating the activity of the compounds inhibiting PI3 kinase alpha activity Inhibition of PI3 kinase is expected to be indicative of activity in treating conditions of excessive or anomalous cell proliferation, such as cancers. See also J. A. Engelman, Nature Reviews Cancer, 2009, 9, 550-562; A. Carnero, Expert Opin. Investig. Drugs, 2009, 18, 1265-1277 and P. Liu et al., Nature Reviews Drug Discovery, 2009, 8, 627-64.
Measurement: IC50 = 658 nM (pChEMBL 6.179999828338623)
Descriptors: MW 537.07, ALogP 4.69, HBA 6, HBD 1, PSA 88.24, QED 0.37
Compound (SMILES): COc1ncc(N2CCc3ncnc(O[C@H]4CCN(C(=O)C5CCOCC5)C4)c3C2)cc1C
InChIKey: VHBAXDNZLJTAHW-IBGZPJMESA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42336
Assay: Inhibition of recombinant PI3Kalpha (unknown origin) using phosphatidyl inositol/n-Octyl-glucoside as substrate measured after 30 mins by KinaseGlo assay
Measurement: IC50 = 1940 nM (pChEMBL 5.710000038146973)
Descriptors: MW 453.54, ALogP 2.16, HBA 8, HBD 0, PSA 89.91, QED 0.68
Compound (SMILES): COc1ncc(N2CCc3ncnc(O[C@H]4CCN(C(=O)C5CCOCC5)C4)c3C2)cc1C(F)(F)F
InChIKey: VKHGYVPRHIWYCB-KRWDZBQOSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42338
Assay: Inhibition of recombinant PI3Kbeta (unknown origin) using phosphatidyl inositol/n-Octyl-glucoside as substrate measured after 60 mins by KinaseGlo assay
Measurement: IC50 = 1330 nM (pChEMBL 5.880000114440918)
Descriptors: MW 507.51, ALogP 2.87, HBA 8, HBD 0, PSA 89.91, QED 0.61
Compound (SMILES): CCC(=O)N1CC[C@H](Oc2ncnc3c2CN(c2cnc(OC)c(C(F)(F)F)c2)CC3)C1
InChIKey: ZADGOAAFZDRNIQ-AWEZNQCLSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42338
Assay: Inhibition of recombinant PI3Kbeta (unknown origin) using phosphatidyl inositol/n-Octyl-glucoside as substrate measured after 60 mins by KinaseGlo assay
Measurement: IC50 = 1710 nM (pChEMBL 5.769999980926514)
Descriptors: MW 451.45, ALogP 2.85, HBA 7, HBD 0, PSA 80.68, QED 0.69
Compound (SMILES): CCC(=O)N1CC[C@H](Nc2ncnc3c2CN(c2cnc(OC)c(C(F)(F)F)c2)CC3)C1
InChIKey: MWKYMZXCGYXLPL-ZDUSSCGKSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (SINGLE PROTEIN), Homo sapiens
UniProt: O00329
Assay: Inhibition of PI3Kdelta (unknown origin) using PIP2 as substrate measured after 1 hr in presence of ATP by ADP-glo luminescence assay
Measurement: IC50 = 1.5 nM (pChEMBL 8.819999694824219)
Descriptors: MW 450.47, ALogP 2.88, HBA 7, HBD 1, PSA 83.48, QED 0.75
Compound (SMILES): COc1ncc(N2CCc3ncnc(N[C@H]4CCN(C(=O)C5CCOCC5)C4)c3C2)cc1C(F)(F)F
InChIKey: PTFKBGVXOIXYQD-INIZCTEOSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42338
Assay: Inhibition of recombinant PI3Kbeta (unknown origin) using phosphatidyl inositol/n-Octyl-glucoside as substrate measured after 60 mins by KinaseGlo assay
Measurement: IC50 = 300 nM (pChEMBL 6.519999980926514)
Descriptors: MW 506.53, ALogP 2.9, HBA 8, HBD 1, PSA 92.71, QED 0.66
Compound (SMILES): CCC(=O)N1CC[C@H](Nc2ncnc3c2CN(c2cnc(OC)c(C)c2)CC3)C1
InChIKey: CEVKJROQTHRTGX-HNNXBMFYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42338
Assay: Inhibition of recombinant PI3Kbeta (unknown origin) using phosphatidyl inositol/n-Octyl-glucoside as substrate measured after 60 mins by KinaseGlo assay
Measurement: IC50 = 951 nM (pChEMBL 6.019999980926514)
Descriptors: MW 396.5, ALogP 2.17, HBA 7, HBD 1, PSA 83.48, QED 0.83
Compound (SMILES): COc1ncc(N2CCc3ncnc(N[C@H]4CCN(C(=O)C5CCOCC5)C4)c3C2)cc1C
InChIKey: RUSHNOUBJBSFQX-SFHVURJKSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42336
Assay: Inhibition of recombinant PI3Kalpha (unknown origin) using phosphatidyl inositol/n-Octyl-glucoside as substrate measured after 30 mins by KinaseGlo assay
Measurement: IC50 = 373 nM (pChEMBL 6.429999828338623)
Descriptors: MW 452.56, ALogP 2.19, HBA 8, HBD 1, PSA 92.71, QED 0.74
Compound (SMILES): CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)NCC2
InChIKey: HNOSPNJMFDPDBU-UHFFFAOYSA-N
Target: Sodium- and chloride-dependent glycine transporter 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P48067
Assay: Glycine Uptake Assay: [3H]-Glycine uptake into recombinant CHO cells expressing human GlyT1: Human GlyT1c expressing recombinant hGlyT1c_5_CHO cells were plated at 20,000 cells per well in 96 well Cytostar-T scintillation microplates (Amersham Biosciences) and cultured to sub-confluency for 24 h. For glycine uptake assays the culture medium was aspirated and the cells were washed once with 100 ul HBSS (Gibco BRL, #14025-050) with 5 mM L-Alanine (Merck #1007). 80 ul HBSS buffer were added, followed by 10 ul inhibitor or vehicle (10% DMSO) and 10 ul [3H]-glycine (TRK71, Amersham Biosciences) to a final concentration of 200 nM for initiation of glycine uptake. The plates were placed in a Wallac Microbeta (PerkinElmer) and continuously counted by solid phase scintillation spectrometry during up to 3 hours. Nonspecific uptake was determined in the presence of 10 uM Org2 4598. IC50 calculations were made by four-parametric logistic nonlinear regressi on analysis (GraphPad Prism).
Measurement: IC50 < 100 nM (pChEMBL 7)
Descriptors: MW 463.04, ALogP 4.36, HBA 4, HBD 2, PSA 67.43, QED 0.54
Compound (SMILES): CC(C)S(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)NCC2
InChIKey: MLTQMZHLSBOWRK-UHFFFAOYSA-N
Target: Sodium- and chloride-dependent glycine transporter 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P48067
Assay: Radioligand Binding Assay: Radioligand binding to human GlyT1c transporter-expressing membranes was carried out as described in Mezler et al., Molecular Pharmacology 74:1705-1715, 2008.More specifically, [3H]-(R)-NPTS radioligand binding to human GlyT1c transporter-expressing membranes was measured in duplicate in a total volume of 200 ul in 96-well plates. To 100 ul of membrane suspension (yielding a final membrane protein concentration of 50 ug/ml) in assay buffer (120 mM NaCl, 2 mM KCl, 10 mM Hepes, 1 mM MgCl2, 1 mM CaCl2, pH 7.5) 80 ul of [3H]-(R)-NPTS (0.5 nM final) were added in assay buffer. For competition experiments 10 ul of buffer or unlabeled compound solution obtained from dilution series of test compounds in DMSO followed. An intermediate 1:10 dilution in assay buffer yielded a final DMSO concentration of 1%. Non-specific binding was determined in the presence of 10 uM Org24598 (or its racemate Org24461) for [3H]-(R)-NPTS.
Measurement: Ki < 100000 nM (pChEMBL 4)
Descriptors: MW 463.04, ALogP 4.36, HBA 4, HBD 2, PSA 67.43, QED 0.57
Compound (SMILES): Cn1cc(S(=O)(=O)NCCOc2ccc3c(c2)C(C2(c4ccc(Cl)cc4)CC(F)(F)C2)NCC3)cn1
InChIKey: JIBSGMNEMKZSAA-UHFFFAOYSA-N
Target: Sodium- and chloride-dependent glycine transporter 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P48067
Assay: Radioligand Binding Assay: Radioligand binding to human GlyT1c transporter-expressing membranes was carried out as described in Mezler et al., Molecular Pharmacology 74:1705-1715, 2008.More specifically, [3H]-(R)-NPTS radioligand binding to human GlyT1c transporter-expressing membranes was measured in duplicate in a total volume of 200 ul in 96-well plates. To 100 ul of membrane suspension (yielding a final membrane protein concentration of 50 ug/ml) in assay buffer (120 mM NaCl, 2 mM KCl, 10 mM Hepes, 1 mM MgCl2, 1 mM CaCl2, pH 7.5) 80 ul of [3H]-(R)-NPTS (0.5 nM final) were added in assay buffer. For competition experiments 10 ul of buffer or unlabeled compound solution obtained from dilution series of test compounds in DMSO followed. An intermediate 1:10 dilution in assay buffer yielded a final DMSO concentration of 1%. Non-specific binding was determined in the presence of 10 uM Org24598 (or its racemate Org24461) for [3H]-(R)-NPTS.
Measurement: Ki < 1000 nM (pChEMBL 6)
Descriptors: MW 537.03, ALogP 3.98, HBA 6, HBD 2, PSA 85.25, QED 0.43
Compound (SMILES): O=S(=O)(NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)NCC2)C1CCCNC1
InChIKey: ODFQJLPCXCOLLD-UHFFFAOYSA-N
Target: Sodium- and chloride-dependent glycine transporter 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P48067
Assay: Radioligand Binding Assay: Radioligand binding to human GlyT1c transporter-expressing membranes was carried out as described in Mezler et al., Molecular Pharmacology 74:1705-1715, 2008.More specifically, [3H]-(R)-NPTS radioligand binding to human GlyT1c transporter-expressing membranes was measured in duplicate in a total volume of 200 ul in 96-well plates. To 100 ul of membrane suspension (yielding a final membrane protein concentration of 50 ug/ml) in assay buffer (120 mM NaCl, 2 mM KCl, 10 mM Hepes, 1 mM MgCl2, 1 mM CaCl2, pH 7.5) 80 ul of [3H]-(R)-NPTS (0.5 nM final) were added in assay buffer. For competition experiments 10 ul of buffer or unlabeled compound solution obtained from dilution series of test compounds in DMSO followed. An intermediate 1:10 dilution in assay buffer yielded a final DMSO concentration of 1%. Non-specific binding was determined in the presence of 10 uM Org24598 (or its racemate Org24461) for [3H]-(R)-NPTS.
Measurement: Ki < 1000 nM (pChEMBL 6)
Descriptors: MW 504.1, ALogP 3.7, HBA 5, HBD 3, PSA 79.46, QED 0.48
Compound (SMILES): CC1(c2ccc(NC(=O)c3ncc(C#N)[nH]3)c(C3=CCCCC3)c2)OCCO1
InChIKey: VIWFELRUSGWYMK-UHFFFAOYSA-N
Target: Macrophage colony-stimulating factor 1 receptor (SINGLE PROTEIN), Mus musculus
UniProt: P09581
Assay: Fluorescence Polarization Competition Immunoassay: An autophosphorylation, fluorescence polarization competition immunoassay was used to determine the potency for c-fms inhibition exhibited by selected compounds of Formula I. The assay was performed in black 96-well microplates (LJL BioSystems). The assay buffer used was 100 mM 4-(2-hydroxyethyl)piperazine 1-ethanesulfonic acid (HEPES), pH 7.5, 1 mM 1,4-dithio-DL-threitol (DTT), 0.01% (v/v) Tween-20. Compounds were diluted in assay buffer containing 4% dimethylsulfoxide (DMSO) just prior to the assay. To each well, 5 μL of compound were added followed by the addition of 3 μL of a mix containing 33 nM c-fms (Johnson & Johnson PRD) and 16.7 mM MgCl2 (Sigma) in assay buffer. The kinase reaction was initiated by adding 2 μL of 5 mM ATP (Sigma) in assay buffer. The final concentrations in the assay were 10 nM c-fms, 1 mM ATP, 5 mM MgCl2, 2% DMSO.
Measurement: IC50 = 3.4 nM (pChEMBL 8.470000267028809)
Descriptors: MW 378.43, ALogP 3.71, HBA 5, HBD 2, PSA 100.03, QED 0.84
Compound (SMILES): CC1(c2ccc(NC(=O)c3ncc(C#N)[nH]3)c(C3=CCCCC3)c2)OCCCO1
InChIKey: VAJNHEUOIQZVIF-UHFFFAOYSA-N
Target: Macrophage colony-stimulating factor 1 receptor (SINGLE PROTEIN), Mus musculus
UniProt: P09581
Assay: Inhibition of c-FMS in mouse BMDM assessed as reduction in CSF-1 stimulated cell proliferation by measuring BrDU incorporation treated for 30 hrs followed by BrDU addition during last 6 hrs of incubation by ELISA
Measurement: IC50 = 44 nM (pChEMBL 7.360000133514404)
Descriptors: MW 392.46, ALogP 4.1, HBA 5, HBD 2, PSA 100.03, QED 0.82
Compound (SMILES): Cc1cc(COc2ccc(S(=O)(=O)NC[C@@H](C(=O)NO)N3CCCCC3)cc2)c2ccccc2n1
InChIKey: XYPVMSYCSIAWKF-DEOSSOPVSA-N
Target: Stromelysin-1 (SINGLE PROTEIN), Homo sapiens
UniProt: P08254
Assay: Enzymatic Assay: The products are solubilized in DMSO at a concentration of 10 mM. A serial 3-fold dilution over 10 points is carried out so as to have a concentration range of from 10 uM to 0.5 nM final concentration. 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 37C. 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 uM. The reaction is carried out in a final volume of 10 ul (4 ul inhibitor, 4 ul substrate, 2 ul enzyme) in a low volume 384-well plate (Corning reference: 3676).
Measurement: IC50 = 4500 nM (pChEMBL 5.349999904632568)
Descriptors: MW 498.61, ALogP 2.76, HBA 7, HBD 3, PSA 120.86, QED 0.31
Compound (SMILES): Cc1cc(COc2ccc(S(=O)(=O)NC[C@@H](C(=O)NO)N3CCOCC3)cc2)c2ccccc2n1
InChIKey: KHOXRRQYROMPSZ-QHCPKHFHSA-N
Target: Matrix metalloproteinase-9 (SINGLE PROTEIN), Homo sapiens
UniProt: P14780
Assay: Enzymatic Assay: The products are solubilized in DMSO at a concentration of 10 mM. A serial 3-fold dilution over 10 points is carried out so as to have a concentration range of from 10 uM to 0.5 nM final concentration. 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 37C. 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 uM. The reaction is carried out in a final volume of 10 ul (4 ul inhibitor, 4 ul substrate, 2 ul enzyme) in a low volume 384-well plate (Corning reference: 3676).
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 500.58, ALogP 1.61, HBA 8, HBD 3, PSA 130.09, QED 0.3
Compound (SMILES): C[C@@H](O)CNC1CCN(c2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nc2)CC1
InChIKey: ZEKYDJPVMYFVGA-GOSISDBHSA-N
Target: Cyclin-dependent kinase 4 (SINGLE PROTEIN), Homo sapiens
UniProt: P11802
Assay: In Vitro Assay: The Cdk4 and Cdk6 inhibitory activity of the compounds is measured with a kinase inhibition assay using recombinant Cdk4/CyclinD1 or Cdk6/CyclinD3 protein complexes. The protein substrate used in the assay is the retinoblastoma protein (Rb). The kinase reactions are carried out in a 96-well filter plate (MSDV N6B50, Millipore). Compounds are serially diluted in kinase buffer (20 mM Tris-HCl, pH 7.4, 50 mM NaCl, 1 mM DTT, 1 mg/ml BSA) and added to the reaction mixture containing 2.5 ng/ml Cdk4/CyclinD1 or Cdk6/CyclinD3, 25 μM ATP, 10 μCi/ml [33P]-ATP, 0.1 μg/ml Rb in the kinase buffer. The mixture is incubated at room temperature for 1 hour and the proteins precipitated with an equal volume of 20% TCA. The plates are washed with 10% TCA according to the manufacturer's instruction and dried at room temperature. The amount of the phosphorylated Rb is determined with a TopCount (PerkinElmer).
Measurement: IC50 = 189 nM (pChEMBL 6.71999979019165)
Descriptors: MW 486.62, ALogP 4.17, HBA 9, HBD 3, PSA 104.02, QED 0.36
Compound (SMILES): Cc1cccc(C(=O)N2C[C@H](Oc3cc(C#N)ccn3)CC[C@H]2C)c1-n1nccn1
InChIKey: QACHRKPZIJHNHU-SJLPKXTDSA-N
Target: Orexin receptor type 2 (SINGLE PROTEIN), Homo sapiens
UniProt: O43614
Assay: Radioligand Binding Assay: The inhibition constant (Ki) is determined using a radioligand binding assay (described in Bergman et. al. Bioorg. Med. Chem. Lett. 2008, 18, 1425-1430).
Measurement: Ki = 3 nM (pChEMBL 8.520000457763672)
Descriptors: MW 402.46, ALogP 2.91, HBA 7, HBD 0, PSA 96.93, QED 0.67
Compound (SMILES): Cc1cccc(-n2nccn2)c1C(=O)N1C[C@H](Oc2cc(C#N)ccn2)CC[C@H]1C
InChIKey: GQCLNKPNLVDVKR-SJLPKXTDSA-N
Target: Orexin/Hypocretin receptor type 1 (SINGLE PROTEIN), Rattus norvegicus
UniProt: P56718
Assay: FLIPR Ca2+ Flux Assay: Chinese hamster ovary (CHO) cells expressing the rat orexin-1 receptor or the human orexin-2 receptor, are grown in Iscove's modified DMEM containing 2 mM L-glutamine, 0.5 g/ml G418, 1% hypoxanthine-thymidine supplement, 100 U/ml penicillin, 100 ug/ml streptomycin and 10% heat-inactivated fetal calf serum (FCS). The cells are seeded at 20,000 cells/well into Becton-Dickinson black 384-well clear bottom sterile plates coated with poly-D-lysine. All reagents were from GIBCO-Invitrogen Corp. The seeded plates are incubated overnight at 37° C. and 5% CO2. Ala-6,12 human orexin-A as the agonist is prepared as a 1 mM stock solution in 1% bovine serum albumin (BSA) and diluted in assay buffer (HBSS containing 20 mM HEPES, 0.1% BSA and 2.5 mM probenecid, pH7.4) for use in the assay at a final concentration of 70 pM. Test compounds are prepared as 10 mM stock solution in DMSO, then diluted in 384-well plates, first in DMSO, then assay buffer. On the day of the assay, cells are washed 3 times with 100 ul assay buffer and then incubated for 60 min (37° C., 5% CO2) in 60 ul assay buffer containing 1 uM Fluo-4AM ester, 0.02% pluronic acid, and 1% BSA. The dye loading solution is then aspirated and cells are washed 3 times with 100 ul assay buffer. 30 ul of that same buffer is left in each well. Within the Fluorescent Imaging Plate Reader (FLIPR, Molecular Devices), test compounds are added to the plate in a volume of 25 ul, incubated for 5 min and finally 25 ul of agonist is added. Fluorescence is measured for each well at 1 second intervals for 5 minutes and the height of each fluorescence peak is compared to the height of the fluorescence peak induced by 70 pM Ala-6,12 orexin-A with buffer in place of antagonist.
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 402.46, ALogP 2.91, HBA 7, HBD 0, PSA 96.93, QED 0.67
Compound (SMILES): C[C@@H]1CC[C@@H](Oc2cc(C#N)ccn2)CN1C(=O)c1cccc(F)c1-n1nccn1
InChIKey: GCPJITKYQCWZPV-GDBMZVCRSA-N
Target: Orexin/Hypocretin receptor type 1 (SINGLE PROTEIN), Rattus norvegicus
UniProt: P56718
Assay: FLIPR Ca2+ Flux Assay: Chinese hamster ovary (CHO) cells expressing the rat orexin-1 receptor or the human orexin-2 receptor, are grown in Iscove's modified DMEM containing 2 mM L-glutamine, 0.5 g/ml G418, 1% hypoxanthine-thymidine supplement, 100 U/ml penicillin, 100 ug/ml streptomycin and 10% heat-inactivated fetal calf serum (FCS). The cells are seeded at 20,000 cells/well into Becton-Dickinson black 384-well clear bottom sterile plates coated with poly-D-lysine. All reagents were from GIBCO-Invitrogen Corp. The seeded plates are incubated overnight at 37° C. and 5% CO2. Ala-6,12 human orexin-A as the agonist is prepared as a 1 mM stock solution in 1% bovine serum albumin (BSA) and diluted in assay buffer (HBSS containing 20 mM HEPES, 0.1% BSA and 2.5 mM probenecid, pH7.4) for use in the assay at a final concentration of 70 pM. Test compounds are prepared as 10 mM stock solution in DMSO, then diluted in 384-well plates, first in DMSO, then assay buffer. On the day of the assay, cells are washed 3 times with 100 ul assay buffer and then incubated for 60 min (37° C., 5% CO2) in 60 ul assay buffer containing 1 uM Fluo-4AM ester, 0.02% pluronic acid, and 1% BSA. The dye loading solution is then aspirated and cells are washed 3 times with 100 ul assay buffer. 30 ul of that same buffer is left in each well. Within the Fluorescent Imaging Plate Reader (FLIPR, Molecular Devices), test compounds are added to the plate in a volume of 25 ul, incubated for 5 min and finally 25 ul of agonist is added. Fluorescence is measured for each well at 1 second intervals for 5 minutes and the height of each fluorescence peak is compared to the height of the fluorescence peak induced by 70 pM Ala-6,12 orexin-A with buffer in place of antagonist.
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 406.42, ALogP 2.75, HBA 7, HBD 0, PSA 96.93, QED 0.66
Compound (SMILES): C[C@@H]1CC[C@@H](Oc2cc(C#N)ccn2)CN1C(=O)c1ccc(F)cc1-n1nccn1
InChIKey: XADMHFYHZAIOGX-RHSMWYFYSA-N
Target: Orexin receptor type 2 (SINGLE PROTEIN), Homo sapiens
UniProt: O43614
Assay: Radioligand Binding Assay: The inhibition constant (Ki) is determined using a radioligand binding assay (described in Bergman et. al. Bioorg. Med. Chem. Lett. 2008, 18, 1425-1430).
Measurement: Ki = 3.5 nM (pChEMBL 8.460000038146973)
Descriptors: MW 406.42, ALogP 2.75, HBA 7, HBD 0, PSA 96.93, QED 0.66
Compound (SMILES): Cc1ccc(C(=O)N2C[C@H](Oc3cc(C#N)ccn3)CC[C@H]2C)c(-n2nccn2)c1
InChIKey: HVKZCWBOKSNHRN-SJLPKXTDSA-N
Target: Orexin receptor type 2 (SINGLE PROTEIN), Homo sapiens
UniProt: O43614
Assay: Radioligand Binding Assay: The inhibition constant (Ki) is determined using a radioligand binding assay (described in Bergman et. al. Bioorg. Med. Chem. Lett. 2008, 18, 1425-1430).
Measurement: Ki = 3.7 nM (pChEMBL 8.430000305175781)
Descriptors: MW 402.46, ALogP 2.91, HBA 7, HBD 0, PSA 96.93, QED 0.67
Compound (SMILES): C[C@@H]1CC[C@@H](Oc2cc(C#N)ccn2)CN1C(=O)c1ccsc1-n1nccn1
InChIKey: CFLCOSGEEDANMY-UKRRQHHQSA-N
Target: Orexin/Hypocretin receptor type 1 (SINGLE PROTEIN), Rattus norvegicus
UniProt: P56718
Assay: FLIPR Ca2+ Flux Assay: Chinese hamster ovary (CHO) cells expressing the rat orexin-1 receptor or the human orexin-2 receptor, are grown in Iscove's modified DMEM containing 2 mM L-glutamine, 0.5 g/ml G418, 1% hypoxanthine-thymidine supplement, 100 U/ml penicillin, 100 ug/ml streptomycin and 10% heat-inactivated fetal calf serum (FCS). The cells are seeded at 20,000 cells/well into Becton-Dickinson black 384-well clear bottom sterile plates coated with poly-D-lysine. All reagents were from GIBCO-Invitrogen Corp. The seeded plates are incubated overnight at 37° C. and 5% CO2. Ala-6,12 human orexin-A as the agonist is prepared as a 1 mM stock solution in 1% bovine serum albumin (BSA) and diluted in assay buffer (HBSS containing 20 mM HEPES, 0.1% BSA and 2.5 mM probenecid, pH7.4) for use in the assay at a final concentration of 70 pM. Test compounds are prepared as 10 mM stock solution in DMSO, then diluted in 384-well plates, first in DMSO, then assay buffer. On the day of the assay, cells are washed 3 times with 100 ul assay buffer and then incubated for 60 min (37° C., 5% CO2) in 60 ul assay buffer containing 1 uM Fluo-4AM ester, 0.02% pluronic acid, and 1% BSA. The dye loading solution is then aspirated and cells are washed 3 times with 100 ul assay buffer. 30 ul of that same buffer is left in each well. Within the Fluorescent Imaging Plate Reader (FLIPR, Molecular Devices), test compounds are added to the plate in a volume of 25 ul, incubated for 5 min and finally 25 ul of agonist is added. Fluorescence is measured for each well at 1 second intervals for 5 minutes and the height of each fluorescence peak is compared to the height of the fluorescence peak induced by 70 pM Ala-6,12 orexin-A with buffer in place of antagonist.
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 394.46, ALogP 2.67, HBA 8, HBD 0, PSA 96.93, QED 0.67
Compound (SMILES): C[C@@H]1CC[C@@H](Oc2cc(C#N)ccn2)CN1C(=O)c1sccc1-n1nccn1
InChIKey: HARDDASKVMKGRN-UKRRQHHQSA-N
Target: Orexin/Hypocretin receptor type 1 (SINGLE PROTEIN), Homo sapiens
UniProt: O43613
Assay: Radioligand Binding Assay: The inhibition constant (Ki) is determined using a radioligand binding assay (described in Bergman et. al. Bioorg. Med. Chem. Lett. 2008, 18, 1425-1430).
Measurement: Ki = 5335 nM (pChEMBL 5.269999980926514)
Descriptors: MW 394.46, ALogP 2.67, HBA 8, HBD 0, PSA 96.93, QED 0.67
Compound (SMILES): C[C@@H]1CC[C@@H](Oc2cc(C#N)ccn2)CN1C(=O)c1cc(Br)ccc1-n1nccn1
InChIKey: VSEQFHTWFOJAHR-RHSMWYFYSA-N
Target: Orexin receptor type 2 (SINGLE PROTEIN), Homo sapiens
UniProt: O43614
Assay: Radioligand Binding Assay: The inhibition constant (Ki) is determined using a radioligand binding assay (described in Bergman et. al. Bioorg. Med. Chem. Lett. 2008, 18, 1425-1430).
Measurement: Ki = 9.1 nM (pChEMBL 8.039999961853027)
Descriptors: MW 467.33, ALogP 3.37, HBA 7, HBD 0, PSA 96.93, QED 0.58
Compound (SMILES): COc1ccc(C(=O)N2C[C@H](Oc3cc(C#N)ccn3)CC[C@H]2C)c(-n2nccn2)n1
InChIKey: DGACJWNMJQVDSN-GDBMZVCRSA-N
Target: Orexin receptor type 2 (SINGLE PROTEIN), Rattus norvegicus
UniProt: P56719
Assay: FLIPR Ca2+ Flux Assay: Chinese hamster ovary (CHO) cells expressing the rat orexin-1 receptor or the human orexin-2 receptor, are grown in Iscove's modified DMEM containing 2 mM L-glutamine, 0.5 g/ml G418, 1% hypoxanthine-thymidine supplement, 100 U/ml penicillin, 100 ug/ml streptomycin and 10% heat-inactivated fetal calf serum (FCS). The cells are seeded at 20,000 cells/well into Becton-Dickinson black 384-well clear bottom sterile plates coated with poly-D-lysine. All reagents were from GIBCO-Invitrogen Corp. The seeded plates are incubated overnight at 37° C. and 5% CO2. Ala-6,12 human orexin-A as the agonist is prepared as a 1 mM stock solution in 1% bovine serum albumin (BSA) and diluted in assay buffer (HBSS containing 20 mM HEPES, 0.1% BSA and 2.5 mM probenecid, pH7.4) for use in the assay at a final concentration of 70 pM. Test compounds are prepared as 10 mM stock solution in DMSO, then diluted in 384-well plates, first in DMSO, then assay buffer. On the day of the assay, cells are washed 3 times with 100 ul assay buffer and then incubated for 60 min (37° C., 5% CO2) in 60 ul assay buffer containing 1 uM Fluo-4AM ester, 0.02% pluronic acid, and 1% BSA. The dye loading solution is then aspirated and cells are washed 3 times with 100 ul assay buffer. 30 ul of that same buffer is left in each well. Within the Fluorescent Imaging Plate Reader (FLIPR, Molecular Devices), test compounds are added to the plate in a volume of 25 ul, incubated for 5 min and finally 25 ul of agonist is added. Fluorescence is measured for each well at 1 second intervals for 5 minutes and the height of each fluorescence peak is compared to the height of the fluorescence peak induced by 70 pM Ala-6,12 orexin-A with buffer in place of antagonist.
Measurement: IC50 = 82 nM (pChEMBL 7.090000152587891)
Descriptors: MW 419.45, ALogP 2.01, HBA 9, HBD 0, PSA 119.05, QED 0.62
Compound (SMILES): COc1ccc(C(=O)N2C[C@H](Oc3cc(C#N)ccn3)CC[C@H]2C)c(C2CC2)n1
InChIKey: PYKHPQALSQAILK-RHSMWYFYSA-N
Target: Orexin receptor type 2 (SINGLE PROTEIN), Rattus norvegicus
UniProt: P56719
Assay: FLIPR Ca2+ Flux Assay: Chinese hamster ovary (CHO) cells expressing the rat orexin-1 receptor or the human orexin-2 receptor, are grown in Iscove's modified DMEM containing 2 mM L-glutamine, 0.5 g/ml G418, 1% hypoxanthine-thymidine supplement, 100 U/ml penicillin, 100 ug/ml streptomycin and 10% heat-inactivated fetal calf serum (FCS). The cells are seeded at 20,000 cells/well into Becton-Dickinson black 384-well clear bottom sterile plates coated with poly-D-lysine. All reagents were from GIBCO-Invitrogen Corp. The seeded plates are incubated overnight at 37° C. and 5% CO2. Ala-6,12 human orexin-A as the agonist is prepared as a 1 mM stock solution in 1% bovine serum albumin (BSA) and diluted in assay buffer (HBSS containing 20 mM HEPES, 0.1% BSA and 2.5 mM probenecid, pH7.4) for use in the assay at a final concentration of 70 pM. Test compounds are prepared as 10 mM stock solution in DMSO, then diluted in 384-well plates, first in DMSO, then assay buffer. On the day of the assay, cells are washed 3 times with 100 ul assay buffer and then incubated for 60 min (37° C., 5% CO2) in 60 ul assay buffer containing 1 uM Fluo-4AM ester, 0.02% pluronic acid, and 1% BSA. The dye loading solution is then aspirated and cells are washed 3 times with 100 ul assay buffer. 30 ul of that same buffer is left in each well. Within the Fluorescent Imaging Plate Reader (FLIPR, Molecular Devices), test compounds are added to the plate in a volume of 25 ul, incubated for 5 min and finally 25 ul of agonist is added. Fluorescence is measured for each well at 1 second intervals for 5 minutes and the height of each fluorescence peak is compared to the height of the fluorescence peak induced by 70 pM Ala-6,12 orexin-A with buffer in place of antagonist.
Measurement: IC50 = 67 nM (pChEMBL 7.170000076293945)
Descriptors: MW 392.46, ALogP 3.31, HBA 6, HBD 0, PSA 88.34, QED 0.78
Compound (SMILES): C[C@@H]1CC[C@@H](Oc2cc(C#N)ccn2)CN1C(=O)c1c(F)cccc1-n1nccn1
InChIKey: TZVZAOSVMDBVLR-GDBMZVCRSA-N
Target: Orexin receptor type 2 (SINGLE PROTEIN), Homo sapiens
UniProt: O43614
Assay: Radioligand Binding Assay: The inhibition constant (Ki) is determined using a radioligand binding assay (described in Bergman et. al. Bioorg. Med. Chem. Lett. 2008, 18, 1425-1430).
Measurement: Ki = 3.4 nM (pChEMBL 8.470000267028809)
Descriptors: MW 406.42, ALogP 2.75, HBA 7, HBD 0, PSA 96.93, QED 0.66
Compound (SMILES): C[C@@H]1CC[C@@H](Oc2cc(C#N)ccn2)CN1C(=O)c1ccc(Cl)cc1-n1nccn1
InChIKey: WCUGLZXLNMVHNW-RHSMWYFYSA-N
Target: Orexin receptor type 2 (SINGLE PROTEIN), Homo sapiens
UniProt: O43614
Assay: Radioligand Binding Assay: The inhibition constant (Ki) is determined using a radioligand binding assay (described in Bergman et. al. Bioorg. Med. Chem. Lett. 2008, 18, 1425-1430).
Measurement: Ki = 1.3 nM (pChEMBL 8.890000343322754)
Descriptors: MW 422.88, ALogP 3.26, HBA 7, HBD 0, PSA 96.93, QED 0.64
Compound (SMILES): C[C@@H]1CC[C@@H](Oc2cc(C#N)ccn2)CN1C(=O)c1sccc1-c1ncccn1
InChIKey: DBURTCDDEKZECI-GDBMZVCRSA-N
Target: Orexin receptor type 2 (SINGLE PROTEIN), Homo sapiens
UniProt: O43614
Assay: Radioligand Binding Assay: The inhibition constant (Ki) is determined using a radioligand binding assay (described in Bergman et. al. Bioorg. Med. Chem. Lett. 2008, 18, 1425-1430).
Measurement: Ki = 5.9 nM (pChEMBL 8.229999542236328)
Descriptors: MW 405.48, ALogP 3.54, HBA 7, HBD 0, PSA 92, QED 0.66
Compound (SMILES): C[C@@H]1CC[C@@H](Oc2cc(C#N)ccn2)CN1C(=O)c1ccsc1-c1ncccn1
InChIKey: XNCRERPJAUJAFZ-GDBMZVCRSA-N
Target: Orexin/Hypocretin receptor type 1 (SINGLE PROTEIN), Rattus norvegicus
UniProt: P56718
Assay: FLIPR Ca2+ Flux Assay: Chinese hamster ovary (CHO) cells expressing the rat orexin-1 receptor or the human orexin-2 receptor, are grown in Iscove's modified DMEM containing 2 mM L-glutamine, 0.5 g/ml G418, 1% hypoxanthine-thymidine supplement, 100 U/ml penicillin, 100 ug/ml streptomycin and 10% heat-inactivated fetal calf serum (FCS). The cells are seeded at 20,000 cells/well into Becton-Dickinson black 384-well clear bottom sterile plates coated with poly-D-lysine. All reagents were from GIBCO-Invitrogen Corp. The seeded plates are incubated overnight at 37° C. and 5% CO2. Ala-6,12 human orexin-A as the agonist is prepared as a 1 mM stock solution in 1% bovine serum albumin (BSA) and diluted in assay buffer (HBSS containing 20 mM HEPES, 0.1% BSA and 2.5 mM probenecid, pH7.4) for use in the assay at a final concentration of 70 pM. Test compounds are prepared as 10 mM stock solution in DMSO, then diluted in 384-well plates, first in DMSO, then assay buffer. On the day of the assay, cells are washed 3 times with 100 ul assay buffer and then incubated for 60 min (37° C., 5% CO2) in 60 ul assay buffer containing 1 uM Fluo-4AM ester, 0.02% pluronic acid, and 1% BSA. The dye loading solution is then aspirated and cells are washed 3 times with 100 ul assay buffer. 30 ul of that same buffer is left in each well. Within the Fluorescent Imaging Plate Reader (FLIPR, Molecular Devices), test compounds are added to the plate in a volume of 25 ul, incubated for 5 min and finally 25 ul of agonist is added. Fluorescence is measured for each well at 1 second intervals for 5 minutes and the height of each fluorescence peak is compared to the height of the fluorescence peak induced by 70 pM Ala-6,12 orexin-A with buffer in place of antagonist.
Measurement: IC50 = 6744 nM (pChEMBL 5.170000076293945)
Descriptors: MW 405.48, ALogP 3.54, HBA 7, HBD 0, PSA 92, QED 0.66
Compound (SMILES): C[C@@H]1CC[C@@H](Oc2cc(C#N)ccn2)CN1C(=O)c1cccc(F)c1-c1ncccn1
InChIKey: LVTXYUFASHOVGN-NVXWUHKLSA-N
Target: Orexin receptor type 2 (SINGLE PROTEIN), Rattus norvegicus
UniProt: P56719
Assay: FLIPR Ca2+ Flux Assay: Chinese hamster ovary (CHO) cells expressing the rat orexin-1 receptor or the human orexin-2 receptor, are grown in Iscove's modified DMEM containing 2 mM L-glutamine, 0.5 g/ml G418, 1% hypoxanthine-thymidine supplement, 100 U/ml penicillin, 100 ug/ml streptomycin and 10% heat-inactivated fetal calf serum (FCS). The cells are seeded at 20,000 cells/well into Becton-Dickinson black 384-well clear bottom sterile plates coated with poly-D-lysine. All reagents were from GIBCO-Invitrogen Corp. The seeded plates are incubated overnight at 37° C. and 5% CO2. Ala-6,12 human orexin-A as the agonist is prepared as a 1 mM stock solution in 1% bovine serum albumin (BSA) and diluted in assay buffer (HBSS containing 20 mM HEPES, 0.1% BSA and 2.5 mM probenecid, pH7.4) for use in the assay at a final concentration of 70 pM. Test compounds are prepared as 10 mM stock solution in DMSO, then diluted in 384-well plates, first in DMSO, then assay buffer. On the day of the assay, cells are washed 3 times with 100 ul assay buffer and then incubated for 60 min (37° C., 5% CO2) in 60 ul assay buffer containing 1 uM Fluo-4AM ester, 0.02% pluronic acid, and 1% BSA. The dye loading solution is then aspirated and cells are washed 3 times with 100 ul assay buffer. 30 ul of that same buffer is left in each well. Within the Fluorescent Imaging Plate Reader (FLIPR, Molecular Devices), test compounds are added to the plate in a volume of 25 ul, incubated for 5 min and finally 25 ul of agonist is added. Fluorescence is measured for each well at 1 second intervals for 5 minutes and the height of each fluorescence peak is compared to the height of the fluorescence peak induced by 70 pM Ala-6,12 orexin-A with buffer in place of antagonist.
Measurement: IC50 = 52 nM (pChEMBL 7.28000020980835)
Descriptors: MW 417.44, ALogP 3.62, HBA 6, HBD 0, PSA 92, QED 0.64
Compound (SMILES): C[C@@H]1CC[C@@H](Oc2cc(C#N)ccn2)CN1C(=O)c1ccc(F)cc1-c1ncccn1
InChIKey: DVQKBFBIBGIHAF-CRAIPNDOSA-N
Target: Orexin/Hypocretin receptor type 1 (SINGLE PROTEIN), Rattus norvegicus
UniProt: P56718
Assay: FLIPR Ca2+ Flux Assay: Chinese hamster ovary (CHO) cells expressing the rat orexin-1 receptor or the human orexin-2 receptor, are grown in Iscove's modified DMEM containing 2 mM L-glutamine, 0.5 g/ml G418, 1% hypoxanthine-thymidine supplement, 100 U/ml penicillin, 100 ug/ml streptomycin and 10% heat-inactivated fetal calf serum (FCS). The cells are seeded at 20,000 cells/well into Becton-Dickinson black 384-well clear bottom sterile plates coated with poly-D-lysine. All reagents were from GIBCO-Invitrogen Corp. The seeded plates are incubated overnight at 37° C. and 5% CO2. Ala-6,12 human orexin-A as the agonist is prepared as a 1 mM stock solution in 1% bovine serum albumin (BSA) and diluted in assay buffer (HBSS containing 20 mM HEPES, 0.1% BSA and 2.5 mM probenecid, pH7.4) for use in the assay at a final concentration of 70 pM. Test compounds are prepared as 10 mM stock solution in DMSO, then diluted in 384-well plates, first in DMSO, then assay buffer. On the day of the assay, cells are washed 3 times with 100 ul assay buffer and then incubated for 60 min (37° C., 5% CO2) in 60 ul assay buffer containing 1 uM Fluo-4AM ester, 0.02% pluronic acid, and 1% BSA. The dye loading solution is then aspirated and cells are washed 3 times with 100 ul assay buffer. 30 ul of that same buffer is left in each well. Within the Fluorescent Imaging Plate Reader (FLIPR, Molecular Devices), test compounds are added to the plate in a volume of 25 ul, incubated for 5 min and finally 25 ul of agonist is added. Fluorescence is measured for each well at 1 second intervals for 5 minutes and the height of each fluorescence peak is compared to the height of the fluorescence peak induced by 70 pM Ala-6,12 orexin-A with buffer in place of antagonist.
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 417.44, ALogP 3.62, HBA 6, HBD 0, PSA 92, QED 0.64