Optimization of the physicochemical and pharmacokinetic attributes in a 6-azauracil series of P2X7 receptor antagonists leading to the discovery of the clinical candidate CE-224,535

被引：63

作者：

Duplantier, Allen J. ^{[1
]}

Dombroski, Mark A. ^{[1
]}

Subramanyam, Chakrapani ^{[1
]}

Beaulieu, Aimee M. ^{[1
]}

Chang, Shang-Poa ^{[1
]}

Gabel, Christopher A. ^{[1
]}

Jordan, Crystal ^{[1
]}

Kalgutkar, Amit S. ^{[1
]}

Kraus, Kenneth G. ^{[1
]}

Labasi, Jeff M. ^{[1
]}

Mussari, Christopher ^{[1
]}

Perregaux, David G. ^{[1
]}

Shepard, Rick ^{[1
]}

Taylor, Timothy J. ^{[1
]}

Trevena, Kristen A. ^{[1
]}

Whitney-Pickett, Carrie ^{[1
]}

Yoon, Kwansik ^{[1
]}

机构：

[1] Pfizer Global Res & Dev, Groton Labs, Groton, CT 06340 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 12期

关键词：

P2X(7); Antagonist; Rheumatoid arthritis; 6-Azauracil; Pharmacokinetic; Log P; PAIN; INFLAMMATION; MICE;

D O I：

10.1016/j.bmcl.2011.04.077

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

High throughput screening (HTS) of our compound file provided an attractive lead compound with modest P2X(7) receptor antagonist potency and high selectivity against a panel of receptors and channels, but also with high human plasma protein binding and a predicted short half-life in humans. Multi-parameter optimization was used to address the potency, physicochemical and pharmacokinetic properties which led to potent P2X(7)R antagonists with good disposition properties. Compound 33 (CE-224,535) was advanced to clinical studies for the treatment of rheumatoid arthritis. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：3708 / 3711

页数：4

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