Design and synthesis of potent and selective pyridazin-4(1H)-one-based PDE10A inhibitors interacting with Tyr683 in the PDE10A selectivity pocket.

@article{Yoshikawa2016DesignAS,
  title={Design and synthesis of potent and selective pyridazin-4(1H)-one-based PDE10A inhibitors interacting with Tyr683 in the PDE10A selectivity pocket.},
  author={Masato Yoshikawa and Takenori Hitaka and Tomoaki Hasui and Makoto Fushimi and Jun-ichi Kunitomo and Hironori Kokubo and Hideyuki Oki and Kosuke Nakashima and Takahiko Taniguchi},
  journal={Bioorganic & medicinal chemistry},
  year={2016},
  volume={24 16},
  pages={
          3447-55
        }
}
Utilizing structure-based drug design techniques, we designed and synthesized phosphodiesterase 10A (PDE10A) inhibitors based on pyridazin-4(1H)-one. These compounds can interact with Tyr683 in the PDE10A selectivity pocket. Pyridazin-4(1H)-one derivative 1 was linked with a benzimidazole group through an alkyl spacer to interact with the OH of Tyr683 and fill the PDE10A selectivity pocket. After optimizing the linker length, we identified 1-(cyclopropylmethyl)-5-[3-(1-methyl-1H-benzimidazol-2… CONTINUE READING
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