2-aryloxy-4-alkylaminopyridines: Discovery of novel corticotropin-releasing factor 1 antagonists

被引：60

作者：

Chen, Yuhpyng L. ^{[1
]}

Obach, R. Scott ^{[3
]}

Braselton, John ^{[2
]}

Corman, Michael L. ^{[1
]}

Forman, James ^{[1
]}

Freeman, Jody ^{[2
]}

Gallaschun, Randall J. ^{[1
]}

Mansbach, Robert ^{[2
]}

Schmidt, Anne W. ^{[2
]}

Sprouse, Jeffrey S. ^{[2
]}

Tingley, F. David, III ^{[2
]}

Winston, Elizabeth ^{[2
]}

Schulz, David W. ^{[2
]}

机构：

[1] Pfizer Inc, PGRD, Dept Med Chem, Groton, CT 06340 USA

[2] Pfizer Inc, PGRD, Dept Neurosci, Groton, CT 06340 USA

[3] Pfizer Inc, PGRD, Dept Drug Metab, Groton, CT 06340 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 05期

关键词：

D O I：

10.1021/jm070579c

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

An orally active clinical candidate of corticotropin-releasing factor 1 (CRF(1)) antagonist 1 showed a significant positive food effect in dog and human after oral administration. Efforts to address the food effect issue led us to explore and discover compounds in series 2 as orally active CRF(1) receptor antagonists, in which some compounds showed improved physicochemical properties while retaining desired pharmacological properties. Compound 3a (CP-376395) was selected for further development, due not only to its reduced food effects but also its greater efficacy in CNS models. Compound 3a was advanced to the clinic. The synthesis of representative potential candidates and their in vitro, ex vivo, and in vivo data are described.

引用

页码：1385 / 1392

页数：8

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