The novel benzopyran class of selective cyclooxygenase-2 inhibitors. Part 2: The second clinical candidate having a shorter and favorable human half-life

被引：269

作者：

Wang, Jane L. ^{[1
]}

Limburg, David ^{[1
]}

Graneto, Matthew J. ^{[1
]}

Springer, John ^{[1
]}

Hamper, Joseph Rogier Bruce ^{[1
]}

Liao, Subo ^{[1
]}

Pawlitz, Jennifer L. ^{[1
]}

Kurumbail, Ravi G. ^{[1
]}

Maziasz, Timothy ^{[1
]}

Talley, John J. ^{[1
]}

Kiefer, James R. ^{[1
]}

Carter, Jeffery ^{[1
]}

机构：

[1] Pfizer Global Res & Dev, Chesterfield, MO 63017 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 23期

关键词：

Cyclooxygenase; COX-2; inhibitor; Clinical candidate; Benzopyran; Half-life; Plasma protein bound; Microsomal; X-ray crystal structure; HYPERALGESIA;

D O I：

10.1016/j.bmcl.2010.07.054

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

In this Letter, we provide the structure-activity relationships, optimization of design, testing criteria, and human half-life data for a series of selective COX-2 inhibitors. During the course of our structure-based drug design efforts, we discovered two distinct binding modes within the COX-2 active site for differently substituted members of this class. The challenge of a undesirably long human half-life for the first clinical candidate 1 t(1/2) = 360 h was addressed by multiple strategies, leading to the discovery of 29b-(S) (SC-75416) with t(1/2) = 34 h. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：7159 / 7163

页数：5

共 7 条

[1]

ASTON KW, 2004, Patent No. 04087687

[2] Evaluation of COX-1/COX-2 selectivity and potency of a new class of COX-2 inhibitors [J].