ABSTRACT
Starting with a high-throughput screening lead, a novel series of CCR5 antagonists was developed utilizing an information-based approach. Improvement of pharmacokinetic properties for the series was pursued by SAR exploration of the lead template. The synthesis, SAR and biological profiles of the series are described.
Subject(s)
Anti-HIV Agents/chemistry , Benzamides/chemistry , CCR5 Receptor Antagonists , HIV Fusion Inhibitors/chemistry , Pyrroles/chemistry , Animals , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacokinetics , Benzamides/chemical synthesis , Benzamides/pharmacology , HIV Fusion Inhibitors/chemical synthesis , HIV Fusion Inhibitors/pharmacokinetics , Humans , Microsomes, Liver/metabolism , Pyrroles/chemical synthesis , Pyrroles/pharmacokinetics , Rats , Receptors, CCR5/metabolism , Structure-Activity RelationshipABSTRACT
Replacement of the cyclic carbamate in our previously disclosed 1-oxa-3,9-diazaspiro[5.5]undecan-2-one template led to the discovery of two novel series of 3,9-diazaspiro[5.5]undecane and undeca-2-one CCR5 antagonists. The synthesis, SAR, and antiviral activities of these two series are described. One compound (32) was found to have attractive combination of antiviral potency, selectivity, and pharmacokinetic profile. The asymmetric synthesis of 32 was also accomplished and both enantiomers were equally potent.
