Piperazine-Based CCR5 Antagonists as HIV-1 Inhibitors. II. Discovery of 1-[(2,4-Dimethyl-3-pyridinyl)carbonyl]-4- methyl-4-[3(<i>S</i>)-methyl-4-[1(<i>S</i>)-[4-(trifluoro- methyl)phenyl]ethyl]-1-piperazinyl]- piperidine <i>N</i>1-Oxide (Sch-350634), an Orally Bioavailable, Potent CCR5 Antagonist

Abstract

Truncation of the original piperidino-2(S)-methyl piperazine lead structure 2, from a family of muscarinic antagonists, gave compound 8 which has improved selectivity for the HIV-1 co-receptor CCR5 over muscarinic receptors. Further optimization for pharmacokinetic properties afforded Sch-350634 (1), a prototypical piperazine-based CCR5 antagonist, which is a potent inhibitor of HIV-1 entry and replication in PBMCs. The title compound (1) has excellent oral bioavailability in rat, dog, and monkey.