Small Molecule Reversible Inhibitors of Bruton’s Tyrosine Kinase (BTK): Structure–Activity Relationships Leading to the Identification of 7-(2-Hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9 H -carbazole-1-carboxamide (BMS-935177)

De Lucca, George V.; Shi, Qing; Liu, Qingjie; Batt, Douglas G.; Beaudoin Bertrand, Myra; Rampulla, Rick; Mathur, Arvind; Discenza, Lorell; D’Arienzo, Celia; Dai, Jun; Obermeier, Mary; Vickery, Rodney; Zhang, Yingru; Yang, Zheng; Marathe, Punit; Tebben, Andrew J.; Muckelbauer, Jodi K.; Chang, ChiehYing J.; Zhang, Huiping; Gillooly, Kathleen; Taylor, Tracy; Pattoli, Mark A.; Skala, Stacey; Kukral, Daniel W.; McIntyre, Kim W.; Salter-Cid, Luisa; Fura, Aberra; Burke, James R.; Barrish, Joel C.; Carter, Percy H.; Tino, Joseph A.

doi:10.1021/acs.jmedchem.6b00722

Small Molecule Reversible Inhibitors of Bruton’s Tyrosine Kinase (BTK): Structure–Activity Relationships Leading to the Identification of 7-(2-Hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9 H -carbazole-1-carboxamide (BMS-935177)

Journal Article · Thu Sep 08 04:00:00 EDT 2016 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.6b00722· OSTI ID:1347757

De Lucca, George V.; Shi, Qing; Liu, Qingjie; Batt, Douglas G.; Beaudoin Bertrand, Myra; Rampulla, Rick; Mathur, Arvind; Discenza, Lorell; D’Arienzo, Celia; Dai, Jun; Obermeier, Mary; Vickery, Rodney; Zhang, Yingru; Yang, Zheng; Marathe, Punit; Tebben, Andrew J.; Muckelbauer, Jodi K.; Chang, ChiehYing J.; Zhang, Huiping; Gillooly, Kathleen more »

Bruton’s tyrosine kinase (BTK) belongs to the TEC family of nonreceptor tyrosine kinases and plays a critical role in multiple cell types responsible for numerous autoimmune diseases. This article will detail the structure–activity relationships (SARs) leading to a novel second generation series of potent and selective reversible carbazole inhibitors of BTK. With an excellent pharmacokinetic profile as well as demonstrated in vivo activity and an acceptable safety profile, 7-(2-hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide 6 (BMS-935177) was selected to advance into clinical development.

Research Organization:: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)

Sponsoring Organization:: INDUSTRY

OSTI ID:: 1347757

Journal Information:: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 17 Vol. 59; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)

Country of Publication:: United States

Language:: ENGLISH

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Small Molecule Reversible Inhibitors of Bruton’s Tyrosine Kinase (BTK): Structure–Activity Relationships Leading to the Identification of 7-(2-Hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9 H -carbazole-1-carboxamide (BMS-935177)

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