title: Structure-activity relationships of N-acyl pyrroloquinolone PDE-5 inhibitors.
abstract: The discovery of the potent and selective PDE-5 inhibitory activity of a pyrroloquinolone scaffold prompted us to explore the SAR of its acyl derivatives. During the course of these studies, three structural series were found with K(i) values for PDE-5 in the subnanomolar range. Systematic modification of one of these leads produced a compound with excellent selectivity for PDE-5 over other phosphodiesterases and oral bioavailability of 15% in male rats. This compound also displayed in vivo efficacy in an anesthetized canine model of erection when dosed intravenously.
authors.affiliation: Drug Discovery, Johnson and Johnson Pharmaceutical Research and Development LLC, 1000 Route 202 S, P.O. Box 300, Raritan, New Jersey 08869, USA. jlanter@prdus.jnj.com
authors.forename: James C
authors.initials: JC
authors.lastname: Lanter
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Sui
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Macielag
authors.forename: James J
authors.initials: JJ
authors.lastname: Fiordeliso
authors.forename: Weiqin
authors.initials: W
authors.lastname: Jiang
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Qiu
authors.forename: Sheela
authors.initials: S
authors.lastname: Bhattacharjee
authors.forename: Patricia
authors.initials: P
authors.lastname: Kraft
authors.forename: T Mathew
authors.initials: TM
authors.lastname: John
authors.forename: Donna
authors.initials: D
authors.lastname: Haynes-Johnson
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Craig
authors.forename: Joanna
authors.initials: J
authors.lastname: Clancy
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002460:Cell Line; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004149:Dioxoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004285:Dogs; D007275:Injections, Intravenous; D008297:Male; D010410:Penile Erection / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000378:metabolism*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C482796:3-benzo(1,3)dioxol-5-yl-9-oxo-1,3,4,9-tetrahydropyrrolo(3,4-b)quinoline-2-carboxylic acid pyridin-4-ylmethyl ester; D004149:Dioxoles; D010726:Phosphodiesterase Inhibitors; D011758:Pyrroles; D015363:Quinolones; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat