Discovery of a pyrazolo[1,5-a]pyrimidine derivative (MT-3014) as a highly selective PDE10A inhibitor via core structure transformation from the stilbene moiety

Y. Koizumi, Yoshihito Tanaka, Takehiko Matsumura, Yoichi Kadoh, Haruko Miyoshi, Mitsuya Hongu, Kei Takedomi, Jun Kotera, Takashi Sasaki, Hiroyuki Taniguchi, Yumi Watanabe, M. Takakuwa, Koki Kojima, Nobuyuki Baba, Itsuko Nakamura, Eiji Kawanishi

研究成果: ジャーナルへの寄稿記事

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We have developed a new class of PDE10A inhibitor, a pyrazolo[1,5-a]pyrimidine derivative MT-3014 (1). A previous compound introduced was deprioritized due to concerns for E/Z-isomerization and glutathione-adduct formation at the core stilbene structure. We discovered pyrazolo [1,5-a] pyrimidine as a new lead scaffold by structure-based drug design utilizing a co-crystal structure with PDE10A. The lead compound was optimized for in vitro activity, solubility, and selectivity against human ether-á-go-go related gene cardiac channel binding. We observed that MT-3014 shows excellent efficacy in rat conditioned avoidance response test and suitable pharmacokinetic properties in rats, especially high brain penetration.

元の言語英語
ページ(範囲)3440-3450
ページ数11
ジャーナルBioorganic and Medicinal Chemistry
27
発行部数15
DOI
出版物ステータス出版済み - 8 1 2019
外部発表Yes

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All Science Journal Classification (ASJC) codes

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

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