Bicyclic amidine inhibitors of nitric oxide synthase: discovery of perhydro-iminopyrindine and perhydro-iminoquinoline as potent, orally active inhibitors of inducible nitric oxide synthase

Ravindra N Guthikonda; Shrenik K Shah; Stephen G Pacholok; John L Humes; Richard A Mumford; Stephan K Grant; Renee M Chabin; Barbara G Green; Nancy Tsou; Richard Ball; Daniel S Fletcher; Silvi Luell; D Euan MacIntyre; Malcolm Maccoss

doi:10.1016/j.bmcl.2005.02.067

Bicyclic amidine inhibitors of nitric oxide synthase: discovery of perhydro-iminopyrindine and perhydro-iminoquinoline as potent, orally active inhibitors of inducible nitric oxide synthase

Bioorg Med Chem Lett. 2005 Apr 15;15(8):1997-2001. doi: 10.1016/j.bmcl.2005.02.067.

Authors

Ravindra N Guthikonda¹, Shrenik K Shah, Stephen G Pacholok, John L Humes, Richard A Mumford, Stephan K Grant, Renee M Chabin, Barbara G Green, Nancy Tsou, Richard Ball, Daniel S Fletcher, Silvi Luell, D Euan MacIntyre, Malcolm Maccoss

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA.

PMID: 15808455
DOI: 10.1016/j.bmcl.2005.02.067

Abstract

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.

MeSH terms

Administration, Oral
Amidines / administration & dosage
Amidines / chemistry*
Animals
Bridged Bicyclo Compounds / administration & dosage
Bridged Bicyclo Compounds / chemistry*
Cell Line
Enzyme Inhibitors / administration & dosage*
Enzyme Inhibitors / pharmacology
Nitric Oxide Synthase / antagonists & inhibitors*
Nitric Oxide Synthase Type II
Pyridines / administration & dosage
Pyridines / chemistry*
Quinolines / administration & dosage
Quinolines / chemistry*
Rats

Substances

Amidines
Bridged Bicyclo Compounds
Enzyme Inhibitors
Pyridines
Quinolines
Nitric Oxide Synthase
Nitric Oxide Synthase Type II
Nos2 protein, rat