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

Yoshikawa M, Hitaka T, Hasui T, Fushimi M, Kunitomo J, Kokubo H, Oki H, Nakashima K, Taniguchi T
Bioorg Med Chem 24 3447-55 (2016)
Cited: 3 times
EuropePMC logo PMID: 27301679

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=0.76nM) and perfect selectivity against other PDEs (>13,000-fold, IC50=>10,000nM). 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.

Articles - 5b4l mentioned but not cited (3)

  1. Codon insertion and deletion functions as a somatic diversification mechanism in human antibody repertoires. Reason DC, Zhou J. Biol Direct 1 24 (2006)
  2. Computer-aided design of multi-target ligands at A1R, A2AR and PDE10A, key proteins in neurodegenerative diseases. Kalash L, Val C, Azuaje J, Loza MI, Svensson F, Zoufir A, Mervin L, Ladds G, Brea J, Glen R, Sotelo E, Bender A. J Cheminform 9 67 (2017)
  3. Synthesis, Crystal Structure, and Biological Evaluation of Novel 5-Hydroxymethylpyrimidines. Stolarczyk M, Matera-Witkiewicz A, Wolska A, Krupińska M, Mikołajczyk A, Pyra A, Bryndal I. Materials (Basel) 14 6916 (2021)




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