Synthesis and evaluation of a series of 4-azaindole-containing p21-activated kinase-1 inhibitors

Bioorg Med Chem Lett. 2016 Aug 1;26(15):3518-24. doi: 10.1016/j.bmcl.2016.06.031. Epub 2016 Jun 15.

Abstract

A series of 4-azaindole-containing p21-activated kinase-1 (PAK1) inhibitors was prepared with the goal of improving physicochemical properties relative to an indole starting point. Indole 1 represented an attractive, non-basic scaffold with good PAK1 affinity and cellular potency but was compromised by high lipophilicity (clogD=4.4). Azaindole 5 was designed as an indole surrogate with the goal of lowering logD and resulted in equipotent PAK1 inhibition with a 2-fold improvement in cellular potency over 1. Structure-activity relationship studies around 5 identified additional 4-azaindole analogs with superior PAK1 biochemical activity (Ki <10nM) and up to 24-fold selectivity for group I over group II PAKs. Compounds from this series showed enhanced permeability, improved aqueous solubility, and lower plasma protein binding over indole 1. The improvement in physicochemical properties translated to a 20-fold decrease in unbound clearance in mouse PK studies for azaindole 5 relative to indole 1.

Keywords: 4-Azaindole; Aminopyrazole; Diaminopyrimidine; Kinase; PAK1.

MeSH terms

  • Animals
  • Dogs
  • Dose-Response Relationship, Drug
  • Humans
  • Indoles / chemical synthesis
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Madin Darby Canine Kidney Cells
  • Mice
  • Mice, Nude
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • p21-Activated Kinases / antagonists & inhibitors*
  • p21-Activated Kinases / metabolism

Substances

  • 4-azaindole
  • Indoles
  • Protein Kinase Inhibitors
  • PAK1 protein, human
  • p21-Activated Kinases