Bioorganic and Medicinal Chemistry Letters p. 441 - 445 (2018)
Update date:2022-08-11
Topics:
Takahara, Satoyuki
Nakagawa, Kiyomi
Uchiyama, Tsugumi
Yoshida, Tomoyuki
Matsumoto, Kazunori
Kawasumi, Yasuo
Mizuguchi, Mineyuki
Obita, Takayuki
Watanabe, Yurie
Hayakawa, Daichi
Gouda, Hiroaki
Mori, Hisashi
Toyooka, Naoki
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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