Design and synthesis of potent and selective pyridazin-4(1H)-one-based PDE10A inhibitors interacting with Tyr683 in the PDE10A selectivity pocket |
| |
Affiliation: | 1. Instituto Nacional de Pesquisas Espaciais, Av. dos Astronautas 1758, São José dos Campos, SP, Brazil;2. Instituto Federal Goiano, - Campus Rio Verde. Rod. Sul Goiana Km 01, Rio Verde, GO, Brazil;3. Universidade Federal de São Paulo, Instituto de Ciência e Tecnologia, R. Talim 330, São José dos Campos, SP, Brazil |
| |
Abstract: | 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-yl)propoxy]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (16f) as having highly potent PDE10A inhibitory activity (IC50 = 0.76 nM) and perfect selectivity against other PDEs (>13,000-fold, IC50 = >10,000 nM). The crystal structure of 16f bound to PDE10A revealed that the benzimidazole moiety was located deep within the PDE10A selectivity pocket and interacted with Tyr683. Additionally, a bidentate interaction existed between the 5-alkoxypyridazin-4(1H)-one moiety and the conserved Gln716 present in all PDEs. |
| |
Keywords: | Phosphodiesterase 10A PDE10A Inhibitors Schizophrenia SBDD |
本文献已被 ScienceDirect 等数据库收录! |
|