Design,synthesis, and evaluation of novel inhibitors for wild-type human serine racemase |
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| Authors: | Satoyuki Takahara Kiyomi Nakagawa Tsugumi Uchiyama Tomoyuki Yoshida Kazunori Matsumoto Yasuo Kawasumi Mineyuki Mizuguchi Takayuki Obita Yurie Watanabe Daichi Hayakawa Hiroaki Gouda Hisashi Mori Naoki Toyooka |
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| Institution: | 1. Graduate School of Innovative Life Science, University of Toyama, Japan;2. Graduate School of Science and Engineering, University of Toyama, Japan;3. Faculty of Engineering, University of Toyama, Japan;4. Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan;5. School of Pharmacy, Showa University, Japan |
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| Abstract: | Most of the endogenous free d-serine (about 90%) in the brain is produced by serine racemase (SR). d-Serine in the brain is involved in neurodegenerative disorders and epileptic states as an endogenous co-agonist of the NMDA-type glutamate receptor. Thus, SR inhibitors are expected to be novel therapeutic candidates for the treatment of these disorders. In this study, we solved the crystal structure of wild-type SR, and tried to identify a new inhibitor of SR by in silico screening using the structural information. As a result, we identified two hit compounds by their in vitro evaluations using wild-type SR.Based on the structure of the more potent hit compound 1, we synthesized 15 derivatives and evaluated their inhibitory activities against wild-type SR. Among them, the compound 9C showed relatively high inhibitory potency for wild-type SR. Compound 9C was a more potent inhibitor than compound 24, which was synthesized by our group based upon the structural information of the mutant-type SR. |
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| Keywords: | Serine racemase inhibitor Corresponding authors at: Graduate School of Innovative Life Science University of Toyama Japan (M Mizuguchi H Mori and N Toyooka) School of Pharmacy Showa University Japan (H Gouda) |
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