1,2-Dihydro-4-quinazolinamines: potent, highly selective inhibitors of inducible nitric oxide synthase which show antiinflammatory activity in vivo.
The discovery of a novel class of nitric oxide synthase (NOS) inhibitors, 2-substituted 1,2-dihydro-4-quinazolinamines, and the related 4'-aminospiro[piperidine-4,2'(1'H)-quinazolin]-4'-amines is described. Members of both series exhibit nanomolar potency and high selectivity for the inducible isoform of the enzyme (i-NOS) relative to the constitutive isoforms in vitro. Efficacy in acute and chronic animal models of inflammatory disease following oral administration has also been demonstrated using these compounds.
Tinker
Alan C
AC
Department of Medicinal Chemistry, AstraZeneca R & D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, UK. Alan.C.Tinker@Astrazeneca.com
Beaton
Haydn G
HG
Boughton-Smith
Nigel
N
Cook
Tony R
TR
Cooper
Sally L
SL
Fraser-Rae
Lynne
L
Hallam
Kay
K
Hamley
Peter
P
McInally
Tom
T
Nicholls
David J
DJ
Pimm
Austen D
AD
Wallace
Alan V
AV
D000208:Acute Disease; D000284:Administration, Oral; D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy; D002460:Cell Line; D002908:Chronic Disease; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007275:Injections, Intravenous; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000588:Amines; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011799:Quinazolines; D013141:Spiro Compounds; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat