Structure-activity relationship (SAR) studies on substituted N-(pyridin-3-yl)-2-amino-isonicotinamides as highly potent and selective glycogen synthase kinase-3 (GSK-3) inhibitors

Bioorg Med Chem Lett. 2023 Feb 1:81:129143. doi: 10.1016/j.bmcl.2023.129143. Epub 2023 Jan 18.

Abstract

In our continuing efforts to explore structure-activity relationships around the novel class of potent, isonicotinamide-based GSK3 inhibitors described in our previous report, we extensively explored structural variations around both 4/5-pyridine substitutions and the amide group. Some analogs were found to have greatly improved pTau lowering potency while retaining high kinase selectivity. In contrast to previous active compounds 1a-c, a close analog 3h did not show in vivo efficacy in a triple-transgenic mouse Alzheimer's disease model. In general, these 2‑pyridinyl amide derivatives were prone to amidase mediated hydrolysis in mouse plasma.

Keywords: Alzheimer’s disease; GSK-3 inhibitor; Isonicotinamide; SAR studies.

MeSH terms

  • Alzheimer Disease*
  • Amides / pharmacology
  • Animals
  • Glycogen Synthase Kinase 3 beta
  • Glycogen Synthase Kinase 3*
  • Mice
  • Mice, Transgenic
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Structure-Activity Relationship

Substances

  • Glycogen Synthase Kinase 3
  • Amides
  • Glycogen Synthase Kinase 3 beta
  • Protein Kinase Inhibitors