Addressing species specific metabolism and solubility issues in a quinoline series of oral PDE4 inhibitors

被引：30

作者：

Lunniss, C. ^{[1
]}

Eldred, C. ^{[1
]}

Aston, N. ^{[1
]}

Craven, A. ^{[1
]}

Gohil, K. ^{[1
]}

Judkins, B. ^{[1
]}

Keeling, S. ^{[1
]}

Ranshaw, L. ^{[1
]}

Robinson, E. ^{[1
]}

Shipley, T. ^{[1
]}

Trivedi, N. ^{[1
]}

机构：

[1] GlaxoSmithKline, Med Res Ctr, Stevenage SG1 2NY, Herts, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 01期

关键词：

PDE4; COPD; Quinoline; Cinnoline; Cynomolgus monkey; PK;

D O I：

10.1016/j.bmcl.2009.11.010

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Species specific conversion of the lead PDE4 inhibitor 1 to the quinolone 3 was identified as the major route of metabolism in the cynomolgus monkey. Modification of the template to give the cinnoline 9 retained potency and selectivity, and greatly improved the pharmacokinetic pro. le in the cynomolgus monkey compared with 1. Additional SAR studies aimed at improving the solubility of 9 are also described. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：137 / 140

页数：4

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