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

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• 作者：Masato Yoshikawa ; ^{masato.yoshikawa@takeda.com" class="auth_mail" title="E-mail the corresponding author} ; Takenori Hitaka ; Tomoaki Hasui ; Makoto Fushimi ; Jun Kunitomo ; Hironori Kokubo ; Hideyuki Oki ; Kosuke Nakashima ; Takahiko Taniguchi
• 关键词：Phosphodiesterase 10A ; PDE10A ; Inhibitors ; Schizophrenia ; SBDD
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 August 2016
• 年：2016
• 卷：24
• 期：16
• 页码：3447-3455
• 全文大小：1814 K

文摘

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.