The discovery of UK-369003, a novel PDE5 inhibitor with the potential for oral bioavailability and dose-proportional pharmacokinetics

被引：22

作者：

Rawson, David J. ^{[1
]}

Ballard, Stephen ^{[3
]}

Barber, Christopher ^{[1
]}

Barker, Laura ^{[3
]}

Beaumont, Kevin ^{[2
]}

Bunnage, Mark ^{[1
]}

Cole, Susan ^{[2
]}

Corless, Martin ^{[1
]}

Denton, Stephen ^{[1
]}

Ellis, David ^{[1
]}

Floc'h, Marion ^{[1
]}

Foster, Laura ^{[3
]}

Gosset, James ^{[2
]}

Holmwood, Frances ^{[1
]}

Lane, Charlotte ^{[1
]}

Leahy, David ^{[3
]}

Mathias, John ^{[1
]}

Maw, Graham ^{[1
]}

Million, William ^{[1
]}

Poinsard, Cedric ^{[1
]}

Price, Jenny ^{[1
]}

Russel, Rachel ^{[3
]}

Street, Stephen ^{[1
]}

Watson, Lesa ^{[1
]}

机构：

[1] Worldwide Med Chem, Sandwich CT13 9NJ, Kent, England

[2] Dept Pharmacokinet Dynam & Metab, Sandwich CT13 9NJ, Kent, England

[3] Pfizer Global Res & Dev, Dept Biol, Sandwich CT13 9NJ, Kent, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2012年 / 20卷 / 01期

关键词：

PDE5; Caco-2; Phosphodiesterase; Oral bioavailability; IN-VITRO; CELL-CULTURE; PHOSPHODIESTERASE-5; ABSORPTION; CACO-2; MODEL;

D O I：

10.1016/j.bmc.2011.10.022

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

This paper describes our recent efforts to design and synthesise potent and selective PDE5 inhibitors and the use of in vitro predictors of clearance, absorption and permeability to maximise the potential for dose-proportional pharmacokinetics and good oral bioavailability in man. Optimisation of the preclinical profile resulted in the identification of UK-369003 (19a) and its nomination as a clinical candidate. The clinical pharmacokinetic and safety profile has enabled us to progress the compound to test its efficacy in patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) and a paper describing its efficacy has recently been published. 2,3 (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：498 / 509

页数：12

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