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

…, S Denton, D Ellis, M Floc'h, L Foster, J Gosset…

文献索引：Rawson, David J.; Ballard, Stephen; Barber, Christopher; Barker, Laura; Beaumont, Kevin; Bunnage, Mark; Cole, Susan; Corless, Martin; Denton, Stephen; Ellis, David; Floc'H, Marion; Foster, Laura; Gosset, James; Holmwood, Frances; Lane, Charlotte; Leahy, David; Mathias, John; Maw, Graham; Million, William; Poinsard, Cedric; Price, Jenny; Russel, Rachel; Street, Stephen; Watson, Lesa Bioorganic and Medicinal Chemistry, 2012 , vol. 20, # 1 p. 498 - 509

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被引用次数: 13

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 ...