Discovery of 4-[(Z)-(4-bromophenyl)- (ethoxyimino)methyl]-1'-[(2,4-dimethyl-3- pyridinyl)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 (K(i) = 2 nM), which possesses subnanomolar activity in blocking viral entry and has excellent antiviral potency versus a panel of primary HIV-1 viral isolates. Compound 1, which has good oral bioavailability in rats, dogs, and monkeys, is proposed as a potential therapeutic agent for the treatment of HIV-1 and has entered human clinical trials.
Palani
A
A
Chemical Research, Drug Safety and Metabolism, and Antiviral Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA. anandan.palani@spcorp.com
Shapiro
S
S
Clader
J W
JW
Greenlee
W J
WJ
Cox
K
K
Strizki
J
J
Endres
M
M
Baroudy
B M
BM
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; D004353:Drug Evaluation, Preclinical; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000821:virology; D008252:Macaca fascicularis; D010091:Oximes; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D010880:Piperidines; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D003497:Cyclic N-Oxides; D010091:Oximes; D010879:Piperazines; D010880:Piperidines; D011725:Pyridines; C438583:Ancriviroc