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
  • 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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