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Discovery of orally available spirodiketopiperazine-based CCR5 antagonists |
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| Authors: | Rena Nishizawa Toshihiko Nishiyama Katsuya Hisaichi Keisuke Hirai Hiromu Habashita Yoshikazu Takaoka Hideaki Tada Kenji Sagawa Shiro Shibayama Kenji Maeda Hiroaki Mitsuya Hisao Nakai Daikichi Fukushima Masaaki Toda |
| Institution: | 1. Minase Research Institute, Ono Pharmaceutical Co., Ltd, Shimamoto, Mishima, Osaka 618-8585, Japan;2. Tsukuba Research Institute, Ono Pharmaceutical Co., Ltd, Ibaraki 300-424, Japan;3. Fukui Research Institute, Ono Pharmaceutical Co., Ltd, Technoport, Yamagishi, Mikuni, Sakai, Fukui 913-8538, Japan;4. Ono Pharmaceutical Co., Ltd, Kyutaro, Chuoh, Osaka 541-0056, Japan;5. Department of Internal Medicine II, Kumamoto University School of Medicine, Kumamoto 860-0811, Japan;6. Experimental Retrovirology Section, HIV & AIDS Malignancy Branch, NCI, National Institutes of Health, Bethesda, MD 20892, USA |
| Abstract: | Using the previously reported novel spirodiketopiperazine scaffold, the design and synthesis of orally available CCR5 antagonists was undertaken. Compounds possessing a carboxylic acid function in the appropriate position showed improved oral exposure (AUC) relative to the initial chemical leads without reduction in the antagonist activity. The optimized compound 40 was found to show potent anti-HIV activity. Full details of structure–activity relationship (SAR) study are presented. |
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