6K9U

Discovery of Pyrazolo[1,5-a]pyrimidine Derivative as a Highly Selective PDE10A Inhibitor

Summary for 6K9U

• Entry DOI: 10.2210/pdb6k9u/pdb
• Descriptor: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A, ZINC ION, MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: enzyme, pde, bbb, brain penetration, crystatl structure, inhibitor, schizophrenia, hydrolase
• Biological source: Rattus norvegicus (Rat)
• Total number of polymer chains: 1
• Total formula weight: 36543.61

Authors

Takedomi, K.,Koizumi, Y. (deposition date: 2019-06-18, release date: 2019-07-17, Last modification date: 2024-03-27)

Primary citation

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.
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., 27:3440-3450, 2019

PubMed 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.

PubMed: 31235264
DOI: 10.1016/j.bmc.2019.06.021

Experimental method

X-RAY DIFFRACTION (2.35 Å)