ABSTRACT
By careful analysis of experimental X-ray ligand crystallographic protein data across several inhibitor series we have discovered a novel, potent and selective series of iNOS inhibitors exemplified by compound 8.
Subject(s)
Enzyme Inhibitors/chemistry , Isoxazoles/chemistry , Nitric Oxide Synthase Type II/antagonists & inhibitors , Pyridines/chemistry , Animals , Binding Sites , Computer Simulation , Crystallography, X-Ray , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Isoxazoles/chemical synthesis , Isoxazoles/pharmacology , Mice , Microsomes, Liver/metabolism , Nitric Oxide Synthase Type II/metabolism , Protein Structure, Tertiary , Pyridines/pharmacology , RatsABSTRACT
A novel series of antagonists of the human P2X7 receptor is described. Modification of substituents enabled identification of compounds selective for the rat P2X7 receptor and provides useful pharmacological tools for evaluation of the role of P2X7 in disease.
Subject(s)
Adamantane/analogs & derivatives , Adamantane/chemical synthesis , Benzamides/chemical synthesis , Interleukin-1beta/antagonists & inhibitors , Purinergic P2 Receptor Antagonists , Adamantane/pharmacology , Animals , Benzamides/pharmacology , Blood Proteins/metabolism , Crystallography, X-Ray , Humans , In Vitro Techniques , Molecular Conformation , Monocytes/metabolism , Protein Binding , Rats , Receptors, Purinergic P2X7 , Structure-Activity RelationshipABSTRACT
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.
