title: Substituted pyrazolopyridopyridazines as orally bioavailable potent and selective PDE5 inhibitors: potential agents for treatment of erectile dysfunction.
abstract: Novel pyrazolopyridopyridazine derivatives have been prepared as potent and selective PDE5 inhibitors. Compound 6 has been identified as a more potent and selective PDE5 inhibitor than sildenafil (1). It is as efficacious as sildenafil in in vitro and in vivo PDE5 inhibition models, and it is orally bioavailable in rats and dogs. The superior isozyme selectivity of 6 is expected to exert less adverse effects in humans when used for erectile dysfunction treatment.
authors.affiliation: Discovery Chemistry, Drug Metabolism and Pharmacokinetics, Drug Safety, and Metabolic and Cardiovascular Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-5400, USA. guixue.yu@bms.com
authors.forename: Guixue
authors.initials: G
authors.lastname: Yu
authors.forename: Helen
authors.initials: H
authors.lastname: Mason
authors.forename: Ximao
authors.initials: X
authors.lastname: Wu
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Saeho
authors.initials: S
authors.lastname: Chong
authors.forename: Bruce
authors.initials: B
authors.lastname: Beyer
authors.forename: Andrew
authors.initials: A
authors.lastname: Henwood
authors.forename: Ronald
authors.initials: R
authors.lastname: Pongrac
authors.forename: Laurie
authors.initials: L
authors.lastname: Seliger
authors.forename: Bin
authors.initials: B
authors.lastname: He
authors.forename: Diane
authors.initials: D
authors.lastname: Normandin
authors.forename: Pam
authors.initials: P
authors.lastname: Ferrer
authors.forename: Rongan
authors.initials: R
authors.lastname: Zhang
authors.forename: Leonard
authors.initials: L
authors.lastname: Adam
authors.forename: William G
authors.initials: WG
authors.lastname: Humphrey
authors.forename: John
authors.initials: J
authors.lastname: Krupinski
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004285:Dogs; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D007172:Erectile Dysfunction / Q000188:drug therapy; D005260:Female; D008297:Male; D010413:Penis / Q000098:blood supply; D011724:Pyridazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011724:Pyridazines; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat