title: Heteroalicyclic carboxamidines as inhibitors of inducible nitric oxide synthase; the identification of (2R)-2-pyrrolidinecarboxamidine as a potent and selective haem-co-ordinating inhibitor.
abstract: Heteroalicyclic carboxamidines were synthesised and evaluated as inhibitors of nitric oxide synthases. (2R)-2-Pyrrolidinecarboxamidine, in particular, was shown to be a highly potent in vitro (IC(50)=0.12 μM) and selective iNOS inhibitor (>100-fold vs both eNOS and nNOS), with probable binding to the key anchoring glutamate residue and co-ordination to the haem iron.
authors.affiliation: GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. Rob.J.Young@gsk.com
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Young
authors.forename: Wendy
authors.initials: W
authors.lastname: Alderton
authors.forename: Anthony D R
authors.initials: AD
authors.lastname: Angell
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Beswick
authors.forename: David
authors.initials: D
authors.lastname: Brown
authors.forename: C Lynn
authors.initials: CL
authors.lastname: Chambers
authors.forename: Miriam C
authors.initials: MC
authors.lastname: Crowe
authors.forename: John
authors.initials: J
authors.lastname: Dawson
authors.forename: Christopher C F
authors.initials: CC
authors.lastname: Hamlett
authors.forename: Simon T
authors.initials: ST
authors.lastname: Hodgson
authors.forename: Savvas
authors.initials: S
authors.lastname: Kleanthous
authors.forename: Richard G
authors.initials: RG
authors.lastname: Knowles
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Russell
authors.forename: Richard
authors.initials: R
authors.lastname: Stocker
authors.forename: James M
authors.initials: JM
authors.lastname: Woolven
mesh_terms: D000578:Amidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006418:Heme / Q000037:antagonists & inhibitors*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000578:Amidines; D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D006418:Heme; D011392:Proline; D052247:Nitric Oxide Synthase Type II; C056291:prolinamide