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Spirodiketopiperazine-based CCR5 antagonist: discovery of an antiretroviral drug candidate |
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| Authors: | Nishizawa Rena Nishiyama Toshihiko Hisaichi Katsuya Minamoto Chiaki Matsunaga Naoki Takaoka Yoshikazu Nakai Hisao Jenkinson Stephen Kazmierski Wieslaw M Tada Hideaki Sagawa Kenji Shibayama Shiro Fukushima Daikichi Maeda Kenji Mitsuya Hiroaki |
| Institution: | a Medicinal Chemistry Research Laboratory, Ono Pharmaceutical Co., Ltd, Shimamoto, Mishima, Osaka 618-8585, Japan b Exploratory Research Laboratory, Ono Pharmaceutical Co., Ltd, Ibaraki 300-424, Japan c GlaxoSmithKline Research and Development, Five Moore Drive, Research Triangle Park, NC 27709-3398, USA d Department of Internal Medicine II, Kumamoto University School of Medicine, Kumamoto 860-0811, Japan e Experimental Retrovirology Section, HIV & AIDS Malignancy Branch, NCI, National Institutes of Health, Bethesda, MD 20892, USA |
| Abstract: | 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. |
| Keywords: | CCR5 Chemokine Anti-HIV |
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