title: 2-aminopyridines as highly selective inducible nitric oxide synthase inhibitors. Differential binding modes dependent on nitrogen substitution.
abstract: 4-Methylaminopyridine (4-MAP) (5) is a potent but nonselective nitric oxide synthase (NOS) inhibitor. While simple N-methylation in this series results in poor activity, more elaborate N-substitution such as with 4-piperidine carbamate or amide results in potent and selective inducible NOS inhibition. Evidently, a flipping of the pyridine ring between these new inhibitors allows the piperidine to interact with different residues and confer excellent selectivity.
authors.affiliation: Medicinal Chemistry, Discovery BioScience, Molecular Biology and Physical and Metabolic Sciences Departments, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leics LE11 5RH, U.K. steve.connolly@astrazeneca.com
authors.forename: Stephen
authors.initials: S
authors.lastname: Connolly
authors.forename: Anders
authors.initials: A
authors.lastname: Aberg
authors.forename: Andrew
authors.initials: A
authors.lastname: Arvai
authors.forename: Haydn G
authors.initials: HG
authors.lastname: Beaton
authors.forename: David R
authors.initials: DR
authors.lastname: Cheshire
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Cook
authors.forename: Sally
authors.initials: S
authors.lastname: Cooper
authors.forename: David
authors.initials: D
authors.lastname: Cox
authors.forename: Peter
authors.initials: P
authors.lastname: Hamley
authors.forename: Phil
authors.initials: P
authors.lastname: Mallinder
authors.forename: Ian
authors.initials: I
authors.lastname: Millichip
authors.forename: David J
authors.initials: DJ
authors.lastname: Nicholls
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Rosenfeld
authors.forename: Stephen A
authors.initials: SA
authors.lastname: St-Gallay
authors.forename: John
authors.initials: J
authors.lastname: Tainer
authors.forename: Alan C
authors.initials: AC
authors.lastname: Tinker
authors.forename: Alan V
authors.initials: AV
authors.lastname: Wallace
mesh_terms: D000631:Aminopyridines / Q000138:chemical synthesis* / Q000737:chemistry; D000818:Animals; D018360:Crystallography, X-Ray; D051379:Mice; D008958:Models, Molecular; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D052247:Nitric Oxide Synthase Type II
chemical_list: D000631:Aminopyridines; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse