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…

Index: 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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Citation Number: 13

Abstract

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 ...