Potent and selective Bruton's tyrosine kinase inhibitors: Discovery of GDC-0834

被引：56

作者：

Young, Wendy B. ^{[1
]}

Barbosa, James ^{[2
]}

Blomgren, Peter ^{[2
]}

Bremer, Meire C. ^{[1
]}

Crawford, James J. ^{[1
]}

Dambach, Donna ^{[1
]}

Gallion, Steve

Hymowitz, Sarah G. ^{[1
]}

Kropf, Jeffrey E. ^{[2
]}

Lee, Seung H. ^{[2
]}

Liu, Lichuan ^{[1
]}

Lubach, Joseph W. ^{[1
]}

Macaluso, Jen ^{[2
]}

Maciejewski, Pat ^{[2
]}

Maurer, Brigitte ^{[1
]}

Mitchell, Scott A. ^{[2
]}

Ortwine, Daniel F. ^{[1
]}

Di Paolo, Julie ^{[2
]}

Reif, Karin ^{[1
]}

Scheerens, Heleen ^{[1
]}

Schmitt, Aaron ^{[2
]}

Sowell, C. Gregory ^{[1
]}

Wang, Xiaojing ^{[1
]}

Wong, Harvey ^{[1
]}

Xiong, Jin-Ming ^{[2
]}

Xu, Jianjun ^{[2
]}

Zhao, Zhongdong ^{[2
]}

Currie, Kevin S. ^{[2
]}

机构：

[1] Genentech Inc, San Francisco, CA 94080 USA

[2] Gilead Sci Inc, Branford, CT 06405 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2015年 / 25卷 / 06期

关键词：

Kinase inhibitor; Bruton's tyrosine kinase; Btk; Rheumatoid arthritis; GDC-0834; Amide hydrolysis; Single dose IND; COLLAGEN-INDUCED ARTHRITIS; B-CELL; INFLAMMATORY DISEASES; IBRUTINIB;

D O I：

10.1016/j.bmcl.2015.01.032

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

SAR studies focused on improving the pharmacokinetic (PK) properties of the previously reported potent and selective Btk inhibitor CGI-1746 (1) resulted in the clinical candidate GDC-0834 (2), which retained the potency and selectivity of CGI-1746, but with much improved PK in preclinical animal models. Structure based design efforts drove this work as modifications to 1 were investigated at both the solvent exposed region as well as 'H3 binding pocket'. However, in vitro metabolic evaluation of 2 revealed a non CYP-mediated metabolic process that was more prevalent in human than preclinical species (mouse, rat, dog, cyno), leading to a high-level of uncertainly in predicting human pharmacokinetics. Due to its promising potency, selectivity, and preclinical efficacy, a single dose IND was filed and 2 was taken in to a single dose phase I trial in healthy volunteers to quickly evaluate the human pharmacokinetics. In human, 2 was found to be highly labile at the exo-cyclic amide bond that links the tetrahydrobenzothiophene moiety to the central aniline ring, resulting in insufficient parent drug exposure. This information informed the back-up program and discovery of improved inhibitors. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：1333 / 1337

页数：5