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
| Autor: | Takehiko Matsumura, Hiroyuki Taniguchi, Takashi Sasaki, Misae Takakuwa, Haruko Miyoshi, Yoichi Kadoh, Eiji Kawanishi, Mitsuya Hongu, Yoshihito Tanaka, Yumi Watanabe, Kei Takedomi, Nobuyuki Baba, Yuuki Koizumi, Jun Kotera, Koki Kojima, Itsuko Nakamura |
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| Rok vydání: | 2019 |
| Předmět: |
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Molecular Pyrimidine Stereochemistry Phosphodiesterase Inhibitors Clinical Biochemistry Pharmaceutical Science Crystallography X-Ray 01 natural sciences Biochemistry Pyrazolopyrimidine chemistry.chemical_compound Structure-Activity Relationship Quinoxaline Hydrolase Drug Discovery Stilbenes Moiety Animals Humans Molecular Biology Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Phosphoric Diester Hydrolases Organic Chemistry In vitro 0104 chemical sciences 010404 medicinal & biomolecular chemistry Pyrimidines chemistry Molecular Medicine Cattle Selectivity Lead compound |
| Zdroj: | Bioorganicmedicinal chemistry. 27(15) |
| ISSN: | 1464-3391 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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