Bicyclic amidine inhibitors of nitric oxide synthase: discovery of perhydro-iminopyrindine and perhydro-iminoquinoline as potent, orally active inhibitors of inducible nitric oxide synthase.
Syntheses and nitric oxide synthase inhibitory activity of cyclic amidines containing 5,6- 6,6- and 7,6-fused systems are described. X-ray structure determination facilitated the assignment of the stereochemistry of the most active compounds perhydro-2-iminoisoquinoline (8a) and perhydro-2-iminopyrindine (10a). Both 8a and 10a are very potent inhibitors of iNOS, with excellent selectivity over eNOS and they are orally active in rats with long duration suitable for once or twice a day dosing.
Guthikonda
Ravindra N
RN
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA.
Shah
Shrenik K
SK
Pacholok
Stephen G
SG
Humes
John L
JL
Mumford
Richard A
RA
Grant
Stephan K
SK
Chabin
Renee M
RM
Green
Barbara G
BG
Tsou
Nancy
N
Ball
Richard
R
Fletcher
Daniel S
DS
Luell
Silvi
S
Euan MacIntyre
D
D
Maccoss
Malcolm
M
D000284:Administration, Oral; D000578:Amidines / Q000008:administration & dosage / Q000737:chemistry*; D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000008:administration & dosage / Q000737:chemistry*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry*; D011804:Quinolines / Q000008:administration & dosage / Q000737:chemistry*; D051381:Rats
D000578:Amidines; D001643:Bridged Bicyclo Compounds; D004791:Enzyme Inhibitors; D011725:Pyridines; D011804:Quinolines; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat