| 15115380 |
Tagat JR, McCombie SW, Nazareno D, Labroli MA, Xiao Y, Steensma RW, Strizki JM, Baroudy BM, Cox K, Lachowicz J, Varty G, Watkins R: Piperazine-based CCR5 antagonists as HIV-1 inhibitors. J Med Chem. 2004 May 6;47(10):2405-8.
IV. Discovery of 1-[(4,6-dimethyl-5-pyrimidinyl) carbonyl]- 4-[4-[2-methoxy-1 (R)-4-(trifluoromethyl) phenyl] ethyl-3 (S)-methyl-1-piperaz inyl]- 4-methylpiperidine (Sch-417690/Sch-D), a potent, highly selective, and orally bioavailable CCR5 antagonist.. The nature and the size of the benzylic substituent are shown to be the key to controlling receptor selectivity (CCR5 vs M1, M2) and potency in the title compounds. Optimization of the lead benzylic methyl compound 3 led to the methoxymethyl analogue 30, which had excellent receptor selectivity and oral bioavailability in rats and monkeys. Compound 30 (Sch-417690/Sch-D), a potent inhibitor of HIV-1 entry into target cells, is currently in clinical trials. |
33(0,1,1,3) |