2. Academic Validation
  3. 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

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

  • Bioorg Med Chem. 2019 Aug 1;27(15):3440-3450. doi: 10.1016/j.bmc.2019.06.021.
Yuuki Koizumi 1,  Yoshihito Tanaka 2,  Takehiko Matsumura 3,  Yoichi Kadoh 2,  Haruko Miyoshi 3,  Mitsuya Hongu 3,  Kei Takedomi 2,  Jun Kotera 3,  Takashi Sasaki 3,  Hiroyuki Taniguchi 4,  Yumi Watanabe 4,  Misae Takakuwa 2,  Koki Kojima 4,  Nobuyuki Baba 3,  Itsuko Nakamura 3,  Eiji Kawanishi 5
Affiliations

Affiliations

  • 1 Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan. Electronic address: [email protected].
  • 2 Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.
  • 3 Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda-shi, Saitama 335-8505, Japan.
  • 4 Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan; Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda-shi, Saitama 335-8505, Japan.
  • 5 Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda-shi, Saitama 335-8505, Japan. Electronic address: [email protected].
PMID: 31235264 DOI: 10.1016/j.bmc.2019.06.021
Abstract

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.

Keywords

Conditioned avoidance response (CAR); Phosphodiesterase (PDE) 10A; Pyrazolopyrimidine; Quinoxaline; Schizophrenia.

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