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Synthesis and in vitro characterization of cinnoline and benzimidazole analogues as phosphodiesterase 10A inhibitors.

ABSTRACT: Fifteen cinnoline analogues and six benzimidazole phosphodiesterase 10A (PDE10A) inhibitors were synthesized as potential PET radiopharmaceuticals and their in vitro activity as PDE10A inhibitors was determined. Nine out of twenty-one compounds were potent inhibitors of PDE10A with IC50 values ranging from 1.5 to 18.6nM. Notably, the IC50 values of compounds 26a, 26b, and 33c were 1.52±0.18, 2.86±0.10, and 3.73±0.60nM, respectively; these three compounds also showed high in vitro selectivity (>1000-fold) for PDE10A over PDE 3A/3B, PDE4A/4B. The high potency and selectivity of these three compounds suggests that they could be radiolabeled with PET radionuclides for further evaluation of their in vivo pharmacological behavior and ability to quantify PDE10A in the brain.

SUBMITTER: Yang H

PROVIDER: S-EPMC4321733 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Synthesis and in vitro characterization of cinnoline and benzimidazole analogues as phosphodiesterase 10A inhibitors.

Yang Hao H Murigi Francis N FN Wang Zhijian Z Li Junfeng J Jin Hongjun H Tu Zhude Z

Bioorganic & medicinal chemistry letters 20141222 4

Fifteen cinnoline analogues and six benzimidazole phosphodiesterase 10A (PDE10A) inhibitors were synthesized as potential PET radiopharmaceuticals and their in vitro activity as PDE10A inhibitors was determined. Nine out of twenty-one compounds were potent inhibitors of PDE10A with IC50 values ranging from 1.5 to 18.6nM. Notably, the IC50 values of compounds 26a, 26b, and 33c were 1.52±0.18, 2.86±0.10, and 3.73±0.60nM, respectively; these three compounds also showed high in vitro selectivity (>1 ...[more]

PMID: 25592707

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