WARNING: This product is for research use only, not for human or veterinary use.
Hodoodo CAT#: H206730
CAS#: 1643368-58-4
Description: BMS-986142 is a potent, selective, reversible BTK inhibitor. BMS-986142 shows BTK IC50 = 0.5nM; human WB IC50 = 90 nM. In molecule of BMS-986142, two atropisomeric centers were rotationally locked to provide a single, stable atropisomer, resulting in enhanced potency and selectivity as well as a reduction in safety liabilities. With significantly enhanced potency and selectivity, excellent in vivo properties and efficacy, and a very desirable tolerability and safety profile, BMS-986142 was advanced into clinical studies.
Hodoodo Cat#: H206730
Name: BMS-986142
CAS#: 1643368-58-4
Chemical Formula: C32H30F2N4O4
Exact Mass: 572.22
Molecular Weight: 572.613
Elemental Analysis: C, 67.12; H, 5.28; F, 6.64; N, 9.78; O, 11.18
Synonym: BMS-986142; BMS 986142; BMS986142.
IUPAC/Chemical Name: (2S,5R,3S)-6-fluoro-5-(3-(8-fluoro-1-methyl-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)-2-methylphenyl)-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide
InChi Key: ZRYMMWAJAFUANM-INIZCTEOSA-N
InChi Code: InChI=1S/C32H30F2N4O4/c1-15-17(7-6-10-24(15)38-30(40)19-8-5-9-21(33)28(19)37(4)31(38)41)25-22(34)14-20(29(35)39)27-26(25)18-12-11-16(32(2,3)42)13-23(18)36-27/h5-10,14,16,36,42H,11-13H2,1-4H3,(H2,35,39)/t16-/m0/s1
SMILES Code: O=C(C1=CC(F)=[C@]([C@]2=CC=CC(N3C(N(C)C4=C(C=CC=C4F)C3=O)=O)=C2C)C5=C1NC6=C5CC[C@H](C(C)(O)C)C6)N
Appearance: Solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
More Info:
| Biological target: | BMS-986142 is a reversible inhibitor of Bruton's tyrosine kinase (BTK) with an IC50 of 0.5 nM. |
| In vitro activity: | Previous studies of BTK inhibition indicate that BTK is essential in FcγR-mediated inflammatory cytokine production. Therefore, this study investigated the effect of BMS-986142 on the ability of peripheral blood mononuclear cells to produce cytokines. BMS-986142 inhibited TNF-α and IL-6 production (IC50, 3 and 4 nM, respectively; Table 2) in these cells stimulated through IgG-containing IC-driven, low affinity-activating FcγR (FcγRIIa and FcγRIIIa). Potencies were equivalent to those measured against BCR-dependent functional endpoints in B cells. LPS stimulation of TNF-α in peripheral blood mononuclear cells was not inhibited by BMS-986142 (IC50, >30,000 nM), consistent with published reports showing TLR4 signaling is not dependent on BTK catalytic activity. Reference: PLoS One. 2017; 12(7): e0181782. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5524405/ |
| In vivo activity: | In this study, 14f (BMS-986142) was shown to block the increase in severe proteinuria (Figure 14A), a measure of the underlying nephritis. Treatment with 14f also provided protection from disease-related death over the course of the treatment (Figure 14B). Histological evaluation of the kidneys at the end of the study demonstrated that treatment with 14f provided robust protection against tubulo-interstitial and glomerular nephritis, as well as inflammatory infiltration, at levels equivalent to those seen with prednisolone (Figure 14C). IgG immune complex deposition, critical in driving disease pathobiology in both this murine model and human lupus nephritis, was prominent in the capillaries of the glomeruli of vehicle control mice. As seen in Figure 14D, histological evaluation revealed that 14f reduced the level of immune complex deposits as effectively as prednisolone. Reference: J Med Chem. 2016 Oct 13;59(19):9173-9200. https://pubmed.ncbi.nlm.nih.gov/27583770/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 76.7 | 133.90 | |
| DMSO:PBS (pH 7.2) (1:3) | 0.3 | 0.44 | |
| DMF | 30.0 | 52.39 | |
| Ethanol | 15.0 | 26.20 |
The following data is based on the product molecular weight 572.61 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
| Formulation protocol: | 1. Gillooly KM, Pulicicchio C, Pattoli MA, Cheng L, Skala S, Heimrich EM, McIntyre KW, Taylor TL, Kukral DW, Dudhgaonkar S, Nagar J, Banas D, Watterson SH, Tino JA, Fura A, Burke JR. Bruton's tyrosine kinase inhibitor BMS-986142 in experimental models of rheumatoid arthritis enhances efficacy of agents representing clinical standard-of-care. PLoS One. 2017 Jul 24;12(7):e0181782. doi: 10.1371/journal.pone.0181782. PMID: 28742141; PMCID: PMC5524405. 2. Watterson SH, De Lucca GV, Shi Q, Langevine CM, Liu Q, Batt DG, Beaudoin Bertrand M, Gong H, Dai J, Yip S, Li P, Sun D, Wu DR, Wang C, Zhang Y, Traeger SC, Pattoli MA, Skala S, Cheng L, Obermeier MT, Vickery R, Discenza LN, D'Arienzo CJ, Zhang Y, Heimrich E, Gillooly KM, Taylor TL, Pulicicchio C, McIntyre KW, Galella MA, Tebben AJ, Muckelbauer JK, Chang C, Rampulla R, Mathur A, Salter-Cid L, Barrish JC, Carter PH, Fura A, Burke JR, Tino JA. Discovery of 6-Fluoro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (BMS-986142): A Reversible Inhibitor of Bruton's Tyrosine Kinase (BTK) Conformationally Constrained by Two Locked Atropisomers. J Med Chem. 2016 Oct 13;59(19):9173-9200. doi: 10.1021/acs.jmedchem.6b01088. Epub 2016 Sep 19. PMID: 27583770. |
| In vitro protocol: | 1. Gillooly KM, Pulicicchio C, Pattoli MA, Cheng L, Skala S, Heimrich EM, McIntyre KW, Taylor TL, Kukral DW, Dudhgaonkar S, Nagar J, Banas D, Watterson SH, Tino JA, Fura A, Burke JR. Bruton's tyrosine kinase inhibitor BMS-986142 in experimental models of rheumatoid arthritis enhances efficacy of agents representing clinical standard-of-care. PLoS One. 2017 Jul 24;12(7):e0181782. doi: 10.1371/journal.pone.0181782. PMID: 28742141; PMCID: PMC5524405. 2. Watterson SH, De Lucca GV, Shi Q, Langevine CM, Liu Q, Batt DG, Beaudoin Bertrand M, Gong H, Dai J, Yip S, Li P, Sun D, Wu DR, Wang C, Zhang Y, Traeger SC, Pattoli MA, Skala S, Cheng L, Obermeier MT, Vickery R, Discenza LN, D'Arienzo CJ, Zhang Y, Heimrich E, Gillooly KM, Taylor TL, Pulicicchio C, McIntyre KW, Galella MA, Tebben AJ, Muckelbauer JK, Chang C, Rampulla R, Mathur A, Salter-Cid L, Barrish JC, Carter PH, Fura A, Burke JR, Tino JA. Discovery of 6-Fluoro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (BMS-986142): A Reversible Inhibitor of Bruton's Tyrosine Kinase (BTK) Conformationally Constrained by Two Locked Atropisomers. J Med Chem. 2016 Oct 13;59(19):9173-9200. doi: 10.1021/acs.jmedchem.6b01088. Epub 2016 Sep 19. PMID: 27583770. |
| In vivo protocol: | 1. Gillooly KM, Pulicicchio C, Pattoli MA, Cheng L, Skala S, Heimrich EM, McIntyre KW, Taylor TL, Kukral DW, Dudhgaonkar S, Nagar J, Banas D, Watterson SH, Tino JA, Fura A, Burke JR. Bruton's tyrosine kinase inhibitor BMS-986142 in experimental models of rheumatoid arthritis enhances efficacy of agents representing clinical standard-of-care. PLoS One. 2017 Jul 24;12(7):e0181782. doi: 10.1371/journal.pone.0181782. PMID: 28742141; PMCID: PMC5524405. 2. Watterson SH, De Lucca GV, Shi Q, Langevine CM, Liu Q, Batt DG, Beaudoin Bertrand M, Gong H, Dai J, Yip S, Li P, Sun D, Wu DR, Wang C, Zhang Y, Traeger SC, Pattoli MA, Skala S, Cheng L, Obermeier MT, Vickery R, Discenza LN, D'Arienzo CJ, Zhang Y, Heimrich E, Gillooly KM, Taylor TL, Pulicicchio C, McIntyre KW, Galella MA, Tebben AJ, Muckelbauer JK, Chang C, Rampulla R, Mathur A, Salter-Cid L, Barrish JC, Carter PH, Fura A, Burke JR, Tino JA. Discovery of 6-Fluoro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (BMS-986142): A Reversible Inhibitor of Bruton's Tyrosine Kinase (BTK) Conformationally Constrained by Two Locked Atropisomers. J Med Chem. 2016 Oct 13;59(19):9173-9200. doi: 10.1021/acs.jmedchem.6b01088. Epub 2016 Sep 19. PMID: 27583770. |
1: Watterson SH, De Lucca GV, Shi Q, Langevine CM, Liu Q, Batt DG, Beaudoin Bertrand M, Gong H, Dai J, Yip S, Li P, Sun D, Wu DR, Wang C, Zhang Y, Traeger SC, Pattoli MA, Skala S, Cheng L, Obermeier MT, Vickery R, Discenza LN, D'Arienzo CJ, Zhang Y, Heimrich E, Gillooly KM, Taylor TL, Pulicicchio C, McIntyre KW, Galella MA, Tebben AJ, Muckelbauer JK, Chang C, Rampulla R, Mathur A, Salter-Cid L, Barrish JC, Carter PH, Fura A, Burke JR, Tino JA. Discovery of 6-Fluoro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl )-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (BMS-986142): A Reversible Inhibitor of Bruton's Tyrosine Kinase (BTK) Conformationally Constrained by Two Locked Atropisomers. J Med Chem. 2016 Oct 13;59(19):9173-9200. PubMed PMID: 27583770.
