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
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
收藏
页码:1333 / 1337
页数:5
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