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]-9H-carbazole-1-carboxamide (BMS-935177)

被引：44

作者：

De Lucca, George V. ^{[1
]}

Shi, Qing ^{[1
]}

Liu, Qingjie ^{[1
]}

Batt, Douglas G. ^{[1
]}

Bertrand, Myra Beaudoin ^{[1
]}

Rampulla, Rick ^{[1
]}

Mathur, Arvind ^{[1
]}

Discenza, Lorell ^{[4
]}

D'Arienzo, Celia ^{[4
]}

Dai, Jun ^{[4
]}

Obermeier, Mary ^{[4
]}

Vickery, Rodney ^{[4
]}

Zhang, Yingru ^{[4
]}

Yang, Zheng ^{[4
]}

Marathe, Punit ^{[4
]}

Tebben, Andrew J. ^{[3
]}

Muckelbauer, Jodi K. ^{[3
]}

Chang, ChiehYing J. ^{[3
]}

Zhang, Huiping ^{[1
]}

Gillooly, Kathleen ^{[2
]}

Taylor, Tracy ^{[2
]}

Pattoli, Mark A. ^{[2
]}

Skala, Stacey ^{[2
]}

Kukral, Daniel W. ^{[5
]}

McIntyre, Kim W. ^{[2
]}

Salter-Cid, Luisa ^{[2
]}

Fura, Aberra ^{[4
]}

Burke, James R. ^{[2
]}

Banish, Joel C. ^{[1
]}

Carter, Percy H. ^{[1
]}

Tino, Joseph A. ^{[1
]}

机构：

[1] Bristol Myers Squibb Res & Dev, Immunosci Discovery Chem, POB 4000, Princeton, NJ 08543 USA

[2] Bristol Myers Squibb Res & Dev, Immunosci Discovery Biol, POB 4000, Princeton, NJ 08543 USA

[3] Bristol Myers Squibb Res & Dev, Mol Struct & Design, Mol Discovery Technol, POB 4000, Princeton, NJ 08543 USA

[4] Bristol Myers Squibb Res & Dev, Metab & Pharmacokinet Dept, Pharmaceut Candidate Optimizat, POB 4000, Princeton, NJ 08543 USA

[5] Bristol Myers Squibb Res & Dev, ECTR CTTO, Dept Imaging, POB 4000, Princeton, NJ 08543 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 59卷 / 17期

关键词：

BIOANALYTICAL PLATFORM; RHEUMATOID-ARTHRITIS; METABOLIC STABILITY; AUTOIMMUNE-DISEASES; CELL ACTIVATION; B-CELLS; DISCOVERY; POTENT; IMMUNODEFICIENCY; MICE;

D O I：

10.1021/acs.jmedchem.6b00722

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 auto-immune 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-dihydroquinazdlin-3-yl)phenyl]-9H-carbazole-1-carboxarnide 6 (BMS-935177) was selected:to advance into clinical development.

引用

页码：7915 / 7935

页数：21

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