ABSTRACT
A series of 3- and 5-imino analogs from oxazepane, thiazepane, and diazepane was prepared and evaluated as inhibitors of human nitric oxide synthesis (NOS). The most potent iNOS inhibitor was the thiazepane analog 25 (IC(50) = 0.19 microM).
Subject(s)
Nitric Oxide Synthase/antagonists & inhibitors , Oxazepines/chemical synthesis , Thiazepines/chemical synthesis , Azirines/chemical synthesis , Azirines/pharmacology , Dihydropyridines/chemical synthesis , Dihydropyridines/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Nitric Oxide Synthase/metabolism , Oxazepines/pharmacology , Thiazepines/pharmacologyABSTRACT
Syntheses and evaluation of pyrrolidin-2-imines and 1,3-thiazolidin-2-imines as inhibitors of nitric oxide synthase (NOS) are discussed. An extensive SAR was established for pyrrolidin-2-imines class of compounds. The amidines came out as the most potent inhibitors in addition to displaying selectivity.
Subject(s)
Enzyme Inhibitors/chemistry , Imines/chemistry , Nitric Oxide Synthase/antagonists & inhibitors , Pyrrolidines/chemistry , Thiazoles/chemistry , Drug Evaluation, Preclinical/methods , Enzyme Inhibitors/pharmacology , Imines/pharmacology , Nitric Oxide Synthase/metabolism , Pyrrolidines/pharmacology , Thiazoles/pharmacologyABSTRACT
Efforts toward the exploration of the title compounds as CCR5 antagonists are disclosed. The basis for such work stems from the fact that cellular proliferation of HIV-1 requires the cooperative assistance of both CCR5 and CD4 receptors. The synthesis and SAR of pyrrolidineacetic acid derivatives as CCR5 antagonists displaying potent binding and antiviral properties in a HeLa cell-based HIV-1 infectivity assay are discussed.
Subject(s)
Anti-HIV Agents/chemical synthesis , CCR5 Receptor Antagonists , HIV-1/drug effects , Pyrrolidines/chemical synthesis , Acetates/chemistry , Anti-HIV Agents/pharmacology , Binding Sites , Cell Division/drug effects , HeLa Cells , Humans , Piperidines/chemical synthesis , Piperidines/pharmacology , Pyrrolidines/chemistry , Structure-Activity RelationshipABSTRACT
Cellular proliferation of HIV-1 requires the cooperative assistance of both the CCR5 and CD4 receptors. Our medicinal chemistry efforts in this area have resulted in the identification of N-alkyl piperidine sulfones as CCR5 antagonists. These compounds display potent binding and show antiviral properties in HIV-1 spread cell-based assays.
