title: Optimization of substituted N-3-benzylimidazoquinazolinone sulfonamides as potent and selective PDE5 inhibitors.
abstract: A previous report from these laboratories identified the N-3-benzylimidazoquinazolinone nucleus as a more selective PDE5 inhibitor template compared to the pyrazolopyrimidine of sildenafil. This paper describes in detail the structure-activity relationships of a set of sulfonamide analogues, several of which are both more potent and more selective PDE5 inhibitors in vitro than sildenafil. The synthesis, in vitro enzyme activity and selectivity, and in vitro functional and preclinical pharmacokinetic assessment of molecules in this series are described.
authors.affiliation: Departments of Discovery Chemistry and Metabolic and Cardiovascular Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 5400, Princeton, New Jersey 08543-5400, USA. david.rotella@bms.com
authors.forename: D P
authors.initials: DP
authors.lastname: Rotella
authors.forename: Z
authors.initials: Z
authors.lastname: Sun
authors.forename: Y
authors.initials: Y
authors.lastname: Zhu
authors.forename: J
authors.initials: J
authors.lastname: Krupinski
authors.forename: R
authors.initials: R
authors.lastname: Pongrac
authors.forename: L
authors.initials: L
authors.lastname: Seliger
authors.forename: D
authors.initials: D
authors.lastname: Normandin
authors.forename: J E
authors.initials: JE
authors.lastname: Macor
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D002417:Cattle; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009132:Muscles; D010413:Penis / Q000187:drug effects / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D010726:Phosphodiesterase Inhibitors; D011799:Quinazolines; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human; C517384:Pde5a protein, rat