Substituted pyrazolopyridopyridazines as orally bioavailable potent and selective PDE5 inhibitors: potential agents for treatment of erectile dysfunction.
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.
Yu
Guixue
G
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
Mason
Helen
H
Wu
Ximao
X
Wang
Jian
J
Chong
Saeho
S
Beyer
Bruce
B
Henwood
Andrew
A
Pongrac
Ronald
R
Seliger
Laurie
L
He
Bin
B
Normandin
Diane
D
Ferrer
Pam
P
Zhang
Rongan
R
Adam
Leonard
L
Humphrey
William G
WG
Krupinski
John
J
Macor
John E
JE
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
D004791:Enzyme Inhibitors; D011724:Pyridazines; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat