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

[Display omitted] 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...

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Published in:Bioorganic & medicinal chemistry 2019-08, Vol.27 (15), p.3440-3450
Main Authors: Koizumi, Yuuki, Tanaka, Yoshihito, Matsumura, Takehiko, Kadoh, Yoichi, Miyoshi, Haruko, Hongu, Mitsuya, Takedomi, Kei, Kotera, Jun, Sasaki, Takashi, Taniguchi, Hiroyuki, Watanabe, Yumi, Takakuwa, Misae, Kojima, Koki, Baba, Nobuyuki, Nakamura, Itsuko, Kawanishi, Eiji
Format: Article
Language:English
Subjects:
Conditioned avoidance response (CAR)
Phosphodiesterase (PDE) 10A
Pyrazolopyrimidine
Quinoxaline
Schizophrenia
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Summary:[Display omitted] 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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2019.06.021