CCR5 antagonists as anti-HIV-1 agents. Part 3: Synthesis and biological evaluation of piperidine-4-carboxamide derivatives.
Replacement of the 5-oxopyrrolidin-3-yl fragment in the previously reported lead structure with a 1-acetylpiperidin-4-yl group led to the discovery of a novel series of potent CCR5 antagonists. Introduction of small hydrophobic substituents on the central phenyl ring increased the binding affinity, providing low to sub-nanomolar CCR5 antagonists. The selected compound 11f showed excellent antiviral activity against CCR5-using HIV-1 replication in human peripheral blood mononuclear cells (EC50=0.59 nM) and an acceptable pharmacokinetic profile in dogs.
Imamura
Shinichi
S
Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd., 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan. imamura_shin-ichi@takeda.co.jp
Nishikawa
Youichi
Y
Ichikawa
Takashi
T
Hattori
Taeko
T
Matsushita
Yoshihiro
Y
Hashiguchi
Shohei
S
Kanzaki
Naoyuki
N
Iizawa
Yuji
Y
Baba
Masanori
M
Sugihara
Yoshihiro
Y
D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D065100:CCR5 Receptor Antagonists; D016466:CHO Cells; D019556:COS Cells; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008297:Male; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D019713:Receptors, CCR5 / Q000737:chemistry; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D010880:Piperidines; D019713:Receptors, CCR5