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Publication Abstract from PubMed

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-a-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.

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.,Koizumi Y, Tanaka Y, Matsumura T, Kadoh Y, Miyoshi H, Hongu M, Takedomi K, Kotera J, Sasaki T, Taniguchi H, Watanabe Y, Takakuwa M, Kojima K, Baba N, Nakamura I, Kawanishi E Bioorg Med Chem. 2019 Jun 19. pii: S0968-0896(19)30495-X. doi:, 10.1016/j.bmc.2019.06.021. PMID:31235264^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.