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.
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.
Tagat
J R
JR
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. jayaram.tagat@spcorp.com
Steensma
R W
RW
McCombie
S W
SW
Nazareno
D V
DV
Lin
S I
SI
Neustadt
B R
BR
Cox
K
K
Xu
S
S
Wojcik
L
L
Murray
M G
MG
Vantuno
N
N
Baroudy
B M
BM
Strizki
J M
JM
D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D065100:CCR5 Receptor Antagonists; D002460:Cell Line; D003497:Cyclic N-Oxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004285:Dogs; D015497:HIV-1 / Q000187:drug effects; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000821:virology; D008252:Macaca fascicularis; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
C438584:1-((2,4-dimethyl-3-pyridinyl)carbonyl)-4-methyl-4-(3-methyl-4-(1-(4-(trifluoromethyl)phenyl)ethyl)-1-piperazinyl)piperidine N1-oxide; D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D003497:Cyclic N-Oxides; D010879:Piperazines