Design, synthesis, and biological evaluation of novel somatostatin receptor subtype-2 agonists: Optimization for potency and risk mitigation of hERG and phospholipidosis

Bioorg Med Chem. 2021 Nov 1:49:116424. doi: 10.1016/j.bmc.2021.116424. Epub 2021 Sep 25.

Abstract

Somatostatin receptors are members of G-protein coupled receptor superfamily. Receptors can be classified into five subtypes, SSTR1 to 5. The highly potent and orally active SSTR2 agonist 7, which had been identified by our group, was found out to have toxicological liabilities such as hERG inhibition and phospholipidosis (PLD). We investigated the relationship between in silico physicochemical properties and hERG and PLD, and explored well-balanced agonists to identify amide 19 and benzimidazole 30. As a result of this exploration, we found out that the value of (cLogP) [2] + (pKa) [2] needs to be less than 110 to mitigate the liabilities.

Keywords: Agonist; G-protein coupled receptor (GPCR); PKa; Phospholipidosis; SSTR2; Somatostatin; cLogP; hERG.

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry
  • Amides / pharmacology*
  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Ether-A-Go-Go Potassium Channels / antagonists & inhibitors*
  • Ether-A-Go-Go Potassium Channels / metabolism
  • Humans
  • Molecular Structure
  • Phospholipids / antagonists & inhibitors*
  • Phospholipids / metabolism
  • Receptors, Somatostatin / agonists*
  • Structure-Activity Relationship

Substances

  • Amides
  • Benzimidazoles
  • Ether-A-Go-Go Potassium Channels
  • Phospholipids
  • Receptors, Somatostatin
  • SSTR2 protein, human
  • benzimidazole