Design, synthesis, and evaluation of novel inhibitors for wild-type human serine racemase

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

doi:10.1016/j.bmcl.2017.12.021

Design, synthesis, and evaluation of novel inhibitors for wild-type human serine racemase

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

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.

Original language	English
Pages (from-to)	441-445
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	28
Issue number	3
DOIs	https://doi.org/10.1016/j.bmcl.2017.12.021
State	Published - 2018/02/01

Keywords

D-Serine
In silico
In vitro
Serine racemase inhibitor

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2017.12.021

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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. (2018). Design, synthesis, and evaluation of novel inhibitors for wild-type human serine racemase. Bioorganic and Medicinal Chemistry Letters, 28(3), 441-445. https://doi.org/10.1016/j.bmcl.2017.12.021

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title = "Design, synthesis, and evaluation of novel inhibitors for wild-type human serine racemase",

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.",

keywords = "D-Serine, In silico, In vitro, Serine racemase inhibitor",

author = "Satoyuki Takahara and Kiyomi Nakagawa and Tsugumi Uchiyama and Tomoyuki Yoshida and Kazunori Matsumoto and Yasuo Kawasumi and Mineyuki Mizuguchi and Takayuki Obita and Yurie Watanabe and Daichi Hayakawa and Hiroaki Gouda and Hisashi Mori and Naoki Toyooka",

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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 2018, 'Design, synthesis, and evaluation of novel inhibitors for wild-type human serine racemase', Bioorganic and Medicinal Chemistry Letters, vol. 28, no. 3, pp. 441-445. https://doi.org/10.1016/j.bmcl.2017.12.021

TY - JOUR

T1 - Design, synthesis, and evaluation of novel inhibitors for wild-type human serine racemase

AU - Takahara, Satoyuki

AU - Nakagawa, Kiyomi

AU - Uchiyama, Tsugumi

AU - Yoshida, Tomoyuki

AU - Matsumoto, Kazunori

AU - Kawasumi, Yasuo

AU - Mizuguchi, Mineyuki

AU - Obita, Takayuki

AU - Watanabe, Yurie

AU - Hayakawa, Daichi

AU - Gouda, Hiroaki

AU - Mori, Hisashi

AU - Toyooka, Naoki

PY - 2018/2/1

Y1 - 2018/2/1

N2 - 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.

AB - 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.

KW - D-Serine

KW - In silico

KW - In vitro

KW - Serine racemase inhibitor

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IS - 3

ER -

Design, synthesis, and evaluation of novel inhibitors for wild-type human serine racemase

Abstract

Keywords

ASJC Scopus subject areas

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