2. Academic Validation
  3. Piperazine-based CCR5 antagonists as HIV-1 inhibitors. II. Discovery of 1-[(2,4-dimethyl-3-pyridinyl)carbonyl]-4- methyl-4-[3(S)-methyl-4-[1(S)-[4-(trifluoromethyl)phenyl]ethyl]-1-piperazinyl]- piperidine N1-oxide (Sch-350634), an orally bioavailable, potent CCR5 antagonist

Piperazine-based CCR5 antagonists as HIV-1 inhibitors. II. Discovery of 1-[(2,4-dimethyl-3-pyridinyl)carbonyl]-4- methyl-4-[3(S)-methyl-4-[1(S)-[4-(trifluoromethyl)phenyl]ethyl]-1-piperazinyl]- piperidine N1-oxide (Sch-350634), an orally bioavailable, potent CCR5 antagonist

  • J Med Chem. 2001 Oct 11;44(21):3343-6. doi: 10.1021/jm0155401.
J R Tagat 1,  R W Steensma,  S W McCombie,  D V Nazareno,  S I Lin,  B R Neustadt,  K Cox,  S Xu,  L Wojcik,  M G Murray,  N Vantuno,  B M Baroudy,  J M Strizki
Affiliations

Affiliation

  • 1 Departments of Chemical Research, Drug Metabolism & Pharmacokinetics, and Antiviral Therapy, Schering-Plough Research Institute, K-15-2B-2800, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA. [email protected]
PMID: 11585438 DOI: 10.1021/jm0155401
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.

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