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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 27 3440-3450 (2019)
Cited: 3 times
EuropePMC logo PMID: 31235264

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-รก-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.

Reviews citing this publication (1)

  1. Insights into the medicinal chemistry of heterocycles integrated with a pyrazolo[1,5-a]pyrimidine scaffold. Hammouda MM, Gaffer HE, Elattar KM. RSC Med Chem 13 1150-1196 (2022)

Articles citing this publication (2)

  1. Efficient Access to 3,5-Disubstituted 7-(Trifluoromethyl)pyrazolo[1,5-a]pyrimidines Involving SNAr and Suzuki Cross-Coupling Reactions. Jismy B, Tikad A, Akssira M, Guillaumet G, Abarbri M. Molecules 25 E2062 (2020)
  2. Synthesis and preclinical evaluation of [11C]MTP38 as a novel PET ligand for phosphodiesterase 7 in the brain. Obokata N, Seki C, Hirata T, Maeda J, Ishii H, Nagai Y, Matsumura T, Takakuwa M, Fukuda H, Minamimoto T, Kawamura K, Zhang MR, Nakajima T, Saijo T, Higuchi M. Eur J Nucl Med Mol Imaging 48 3101-3112 (2021)


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