title: The discovery of UK-369003, a novel PDE5 inhibitor with the potential for oral bioavailability and dose-proportional pharmacokinetics.
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 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.
authors.affiliation: Worldwide Medicinal Chemistry, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK. davidrawson1@gmail.com
authors.forename: David J
authors.initials: DJ
authors.lastname: Rawson
authors.forename: Stephen
authors.initials: S
authors.lastname: Ballard
authors.forename: Christopher
authors.initials: C
authors.lastname: Barber
authors.forename: Laura
authors.initials: L
authors.lastname: Barker
authors.forename: Kevin
authors.initials: K
authors.lastname: Beaumont
authors.forename: Mark
authors.initials: M
authors.lastname: Bunnage
authors.forename: Susan
authors.initials: S
authors.lastname: Cole
authors.forename: Martin
authors.initials: M
authors.lastname: Corless
authors.forename: Stephen
authors.initials: S
authors.lastname: Denton
authors.forename: David
authors.initials: D
authors.lastname: Ellis
authors.forename: Marion
authors.initials: M
authors.lastname: Floc'h
authors.forename: Laura
authors.initials: L
authors.lastname: Foster
authors.forename: James
authors.initials: J
authors.lastname: Gosset
authors.forename: Frances
authors.initials: F
authors.lastname: Holmwood
authors.forename: Charlotte
authors.initials: C
authors.lastname: Lane
authors.forename: David
authors.initials: D
authors.lastname: Leahy
authors.forename: John
authors.initials: J
authors.lastname: Mathias
authors.forename: Graham
authors.initials: G
authors.lastname: Maw
authors.forename: William
authors.initials: W
authors.lastname: Million
authors.forename: Cedric
authors.initials: C
authors.lastname: Poinsard
authors.forename: Jenny
authors.initials: J
authors.lastname: Price
authors.forename: Rachel
authors.initials: R
authors.lastname: Russel
authors.forename: Stephen
authors.initials: S
authors.lastname: Street
authors.forename: Lesa
authors.initials: L
authors.lastname: Watson
mesh_terms: D000284:Administration, Oral; D001682:Biological Availability; D002460:Cell Line; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000737:chemistry* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D059411:Lower Urinary Tract Symptoms / Q000188:drug therapy / Q000209:etiology; D008297:Male; D058986:Phosphodiesterase 5 Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D011470:Prostatic Hyperplasia / Q000150:complications; D011744:Pyrimidinones / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D013449:Sulfonamides / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: C553931:1-(6-ethoxy-5-(3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo(4,3-d)pyrimidin-5-yl)-3-pyridyl sulphonyl)-4-ethylpiperazine; D058986:Phosphodiesterase 5 Inhibitors; D011744:Pyrimidinones; D013449:Sulfonamides; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5