Benzothiophene derivatives as phosphodiesterase 10A (PDE10A) inhibitors: Hit-to-lead studies

Bioorg Med Chem Lett. 2019 Jun 1;29(11):1419-1422. doi: 10.1016/j.bmcl.2019.03.021. Epub 2019 Mar 19.

Abstract

A novel series of benzothiophene derivatives was discovered as phosphodiesterase 10A (PDE10A) inhibitors. Structure-activity relationship studies on high-throughput screening hit compound 1 led to the identification of 7-acetyl-3-methyl-N-(quinolin-2-yl)-1-benzothiophene-2-carboxamide (16), with potent inhibitory activity (PDE10A IC50 = 7.6 nM) and selectivity (>1300-fold selectivity over the other tested phosphodiesterases). In addition, a novel methyl-induced conformational alteration of the benzothiophene-2-carboxamide derivatives is reported.

Keywords: Benzothiophene; Conformational alteration; Hit-to-lead studies; PDE10A inhibitors; Phosphodiesterase 10A inhibitors.

MeSH terms

  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Phosphodiesterase Inhibitors / chemical synthesis
  • Phosphodiesterase Inhibitors / chemistry
  • Phosphodiesterase Inhibitors / pharmacology*
  • Phosphoric Diester Hydrolases / metabolism*
  • Structure-Activity Relationship
  • Thiophenes / chemical synthesis
  • Thiophenes / chemistry
  • Thiophenes / pharmacology*

Substances

  • Phosphodiesterase Inhibitors
  • Thiophenes
  • benzothiophene
  • PDE10A protein, human
  • Phosphoric Diester Hydrolases