| 11585438 |
Tagat JR, Steensma RW, McCombie SW, Nazareno DV, Lin SI, Neustadt BR, Cox K, Xu S, Wojcik L, Murray MG, Vantuno N, Baroudy BM, Strizki JM: Piperazine-based CCR5 antagonists as HIV-1 inhibitors. J Med Chem. 2001 Oct 11;44(21):3343-6.
II. Discovery of 1-[(2,4-dimethyl-3-pyridinyl) carbonyl]-4- methyl-4-[3 (S)-methyl-4-[1 (S)-[4-(trifluoromethyl) phenyl] ethyl]-1-piperazi nyl]- piperidine N1-oxide (Sch-350634), an orally bioavailable, potent CCR5 antagonist.. 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. |
144(1,3,3,4) |