Design and synthesis of pyridin-2-ylmethylaminopiperidin-1-ylbutyl amide CCR5 antagonists that are potent inhibitors of M-tropic (R5) HIV-1 replication
A series of CCR5 antagonists were optimized for potent inhibition of R5 HIV-1 replication in peripheral blood mononuclear cells. Compounds that met acceptable ADME criteria, selectivity, human plasma protein binding, potency shift in the presence of α-glycoprotein were evaluated in rat and dog pharmacokinetics.
Synthesis, SAR, and biological evaluation of oximino-piperidino-piperidine amides. 1. Orally bioavailable CCR5 receptor antagonists with potent anti-HIV activity
We previously reported the discovery of 4-[(Z)-(4-bromophenyl)(ethoxyimino)methyl]-1′-[(2,4-dimethyl-3 -pyridinyl)carbonyl]-4′-methyl-1,4′-bipipefidine N-oxide 1 (SCH 351125) as an orally bioavailable human CCR5 antagonist for the treatment of HIV-1 infec
Palani, Anandan,Shapiro, Sherry,Josien, Hubert,Bara, Thomas,Clader, John W.,Greenlee, William J.,Cox, Kathleen,Strizki, Julie M.,Baroudy, Bahige M.
p. 3143 - 3160
(2007/10/03)
Discovery of 4-[(Z)-(4-bromophenyl)(ethoxyimino)methyl]-1′-[(2,4-dimethyl- 3pyridinyl)carbonyl]-4′-methyl-1,4′bipiperidine N-oxide (SCH 351125): An orally bioavailable human CCR5 antagonist for the treatment of HIV infection
Structure - activity studies on piperidino-piperidine 3 led to the discovery of SCH 351125 (1), a selective CCR5 antagonist with potent activity against RANTES binding (Ki=2 nM), which possesses subnanomolar activity in blocking viral entry and