ABSTRACT
Syntheses and nitric oxide synthase inhibitory activity of cyclic amidines containing 5,6- 6,6- and 7,6-fused systems are described. X-ray structure determination facilitated the assignment of the stereochemistry of the most active compounds perhydro-2-iminoisoquinoline (8a) and perhydro-2-iminopyrindine (10a). Both 8a and 10a are very potent inhibitors of iNOS, with excellent selectivity over eNOS and they are orally active in rats with long duration suitable for once or twice a day dosing.
Subject(s)
Amidines/chemistry , Bridged Bicyclo Compounds/chemistry , Enzyme Inhibitors/administration & dosage , Nitric Oxide Synthase/antagonists & inhibitors , Pyridines/chemistry , Quinolines/chemistry , Administration, Oral , Amidines/administration & dosage , Animals , Bridged Bicyclo Compounds/administration & dosage , Cell Line , Enzyme Inhibitors/pharmacology , Nitric Oxide Synthase Type II , Pyridines/administration & dosage , Quinolines/administration & dosage , RatsABSTRACT
Synthesis of analogs containing more rigid bicyclic piperidine replacements for the 4-benzyloxycarbonyl-(ethyl)amino-piperidine moiety of the CCR5 antagonist structure, 1, is described. Although similar binding affinity to the lead was achieved with some analogs they were overall less potent anti-HIV agents suggesting that other features besides CCR5 binding are required for good anti-viral activity.
Subject(s)
Anti-HIV Agents/chemical synthesis , CCR5 Receptor Antagonists , Sulfones/chemical synthesis , Anti-HIV Agents/pharmacology , Butanes/chemical synthesis , Butanes/pharmacology , Dose-Response Relationship, Drug , Inhibitory Concentration 50 , Piperidines/chemical synthesis , Piperidines/pharmacology , Structure-Activity Relationship , Sulfones/pharmacology , Viruses/drug effectsABSTRACT
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.
