5x2l

Publication Abstract from PubMed

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.

Design, synthesis, and evaluation of novel inhibitors for wild-type human serine racemase.,Takahara S, Nakagawa K, Uchiyama T, Yoshida T, Matsumoto K, Kawasumi Y, Mizuguchi M, Obita T, Watanabe Y, Hayakawa D, Gouda H, Mori H, Toyooka N Bioorg Med Chem Lett. 2017 Dec 13. pii: S0960-894X(17)31180-0. doi:, 10.1016/j.bmcl.2017.12.021. PMID:29277459^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.