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

详细信息    查看全文

• 作者：David J. Rawson^a ; ^{davidrawson1@gmail.com} ; Stephen Ballard^c ; Christopher Barber^a ; Laura Barker^c ; Kevin Beaumont^b ; Mark Bunnage^a ; Susan Cole^b ; Martin Corless^a ; Stephen Denton^a ; David Ellis^a ; Marion Floc&rsquo ; h^a ; Laura Foster^c ; James Gosset^b ; Frances Holmwood^a ; Charlotte Lane^a ; David Leahy^c ; John Mathias^a ; Graham Maw^a ; William Million^a ; Cedric Poinsard^a ; Jenny Price^a ; Rachel Russel^c ; Stephen Street^a ; Lesa Watson^a
• 关键词：PDE5 ; Caco-2 ; Phosphodiesterase ; Oral bioavailability
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 出版时间：1 January, 2012
• 年：2012
• 卷：20
• 期：1
• 页码：498-509
• 全文大小：2332 K

文摘

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 (trong class=""boldFont"">19atrong>) 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.