Spirodiketopiperazine-based CCR5 antagonist: discovery of an antiretroviral drug candidate.
Following the discovery that hydroxylated derivative 3 (Fig. 1) was one of the oxidative metabolites of the original lead 1, it was found that hydroxylated compound 4 possesses higher in vitro anti-HIV potency than the corresponding non-hydroxylated compound 2. Structural hybridation of 4 with the orally available analog 5 resulted in another orally-available spirodiketopiperazine CCR5 antagonist 6a that possesses more favorable pharmaceutical profile for use as a drug candidate.
Medicinal Chemistry Research Laboratory, Ono Pharmaceutical Co., Ltd, Shimamoto, Mishima, Osaka 618-8585, Japan. r.nishizawa@ono.co.jp
Rena
R
Nishizawa
Toshihiko
T
Nishiyama
Katsuya
K
Hisaichi
Chiaki
C
Minamoto
Naoki
N
Matsunaga
Yoshikazu
Y
Takaoka
Hisao
H
Nakai
Stephen
S
Jenkinson
Wieslaw M
WM
Kazmierski
Hideaki
H
Tada
Kenji
K
Sagawa
Shiro
S
Shibayama
Daikichi
D
Fukushima
Kenji
K
Maeda
Hiroaki
H
Mitsuya
D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D065100:CCR5 Receptor Antagonists; D045744:Cell Line, Tumor; D054659:Diketopiperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D016655:HIV Core Protein p24 / Q000378:metabolism; D015497:HIV-1 / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D019713:Receptors, CCR5 / Q000378:metabolism; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism
D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D054659:Diketopiperazines; D016655:HIV Core Protein p24; D019713:Receptors, CCR5; D013141:Spiro Compounds
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