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-(trifluoro-methyl)phenyl]ethyl]-1-piperazinyl]-piperidine N1-oxide (Sch-350634), an orally bioavailable, potent CCR5 antagonist

Authors
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
Citation
Jr. Tagat et al., 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-(trifluoro-methyl)phenyl]ethyl]-1-piperazinyl]-piperidine N1-oxide (Sch-350634), an orally bioavailable, potent CCR5 antagonist, J MED CHEM, 44(21), 2001, pp. 3343-3346
Citations number
15
Categorie Soggetti
Chemistry & Analysis
Journal title
JOURNAL OF MEDICINAL CHEMISTRY
ISSN journal
00222623 → ACNP
Volume
44
Issue
21
Year of publication
2001
Pages
3343 - 3346
Database
ISI
SICI code
0022-2623(20011011)44:21<3343:PCAAHI>2.0.ZU;2-Q
Abstract
Truncation of the original piperidino-2(S)-methyl piperazine lead structure 2, from a family of muscarinic antagonists, gave compound 8 which has impr oved 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 inhibi tor of HIV-1 entry and replication in PBMCs. The title compound (1) has exc ellent oral bioavailability in rat, dog, and monkey.