期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 20, 期 23, 页码 7159-7163出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2010.07.054
关键词
Cyclooxygenase; COX-2 inhibitor; Clinical candidate; Benzopyran; Half-life; Plasma protein bound; Microsomal; X-ray crystal structure
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.
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