Discovery and development of neuronal nitric oxide synthase inhibitors.
The role of neuronally derived nitric oxide (NO) in neurotransmission and neural injury remains an area of active investigation. NO generation has been postulated to be involved in the deleterious events surrounding ischemia/reperfusion injury either directly or via the production of more reactive oxidants such as peroxynitrite. In our search for novel therapeutics for the treatment of a variety of neurological diseases including stroke, we have discovered novel, potent, and selective inhibitors of the neuronal nitric oxide synthase (nNOS) isoform. These compounds have proven to be effective in models of ischemia/reperfusion supporting the role of nNOS in these processes. The effects of these compounds as well as additional aspects critical to their development will be presented.
Reif
D W
DW
AstraZeneca R and D Boston, Worcester, MA 01605, USA. david.reif@astrazeneca.com
McCarthy
D J
DJ
Cregan
E
E
Macdonald
J E
JE
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000201:enzymology; D004195:Disease Models, Animal; D004285:Dogs; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D007700:Kinetics; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052248:Nitric Oxide Synthase Type I; D051381:Rats; D020521:Stroke / Q000188:drug therapy / Q000201:enzymology; D044005:Tetrahydroisoquinolines; D013876:Thiophenes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
C412691:AR-R 18512; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D018696:Neuroprotective Agents; D044005:Tetrahydroisoquinolines; D013876:Thiophenes; C496320:NOS1 protein, human; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; C496322:Nos1 protein, rat