title: 1,2-Dihydro-4-quinazolinamines: potent, highly selective inhibitors of inducible nitric oxide synthase which show antiinflammatory activity in vivo.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca R & D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, UK. Alan.C.Tinker@Astrazeneca.com
authors.forename: Alan C
authors.initials: AC
authors.lastname: Tinker
authors.forename: Haydn G
authors.initials: HG
authors.lastname: Beaton
authors.forename: Nigel
authors.initials: N
authors.lastname: Boughton-Smith
authors.forename: Tony R
authors.initials: TR
authors.lastname: Cook
authors.forename: Sally L
authors.initials: SL
authors.lastname: Cooper
authors.forename: Lynne
authors.initials: L
authors.lastname: Fraser-Rae
authors.forename: Kay
authors.initials: K
authors.lastname: Hallam
authors.forename: Peter
authors.initials: P
authors.lastname: Hamley
authors.forename: Tom
authors.initials: T
authors.lastname: McInally
authors.forename: David J
authors.initials: DJ
authors.lastname: Nicholls
authors.forename: Austen D
authors.initials: AD
authors.lastname: Pimm
authors.forename: Alan V
authors.initials: AV
authors.lastname: Wallace
mesh_terms: 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
chemical_list: 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