Identification of potent and selective amidobipyridyl inhibitors of protein kinase D

J Med Chem. 2010 Aug 12;53(15):5422-38. doi: 10.1021/jm100076w.

Abstract

The synthesis and biological evaluation of potent and selective PKD inhibitors are described herein. The compounds described in the present study selectively inhibit PKD among other putative HDAC kinases. The PKD inhibitors of the present study blunt phosphorylation and subsequent nuclear export of HDAC4/5 in response to diverse agonists. These compounds further establish the central role of PKD as an HDAC4/5 kinase and enhance the current understanding of cardiac myocyte signal transduction. The in vivo efficacy of a representative example compound on heart morphology is reported herein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2,2'-Dipyridyl / analogs & derivatives*
  • 2,2'-Dipyridyl / chemical synthesis
  • 2,2'-Dipyridyl / pharmacokinetics
  • 2,2'-Dipyridyl / pharmacology
  • Active Transport, Cell Nucleus
  • Administration, Oral
  • Aminopyridines / chemical synthesis*
  • Aminopyridines / pharmacokinetics
  • Aminopyridines / pharmacology
  • Animals
  • Antihypertensive Agents / chemical synthesis
  • Antihypertensive Agents / pharmacokinetics
  • Antihypertensive Agents / pharmacology
  • Blood Pressure / drug effects
  • Cardiomegaly / drug therapy
  • Cardiomegaly / enzymology
  • Cardiomegaly / pathology
  • Cell Nucleus / metabolism
  • Histone Deacetylases / metabolism
  • Isoenzymes / antagonists & inhibitors
  • Male
  • Models, Molecular
  • Muscle Cells / drug effects
  • Muscle Cells / metabolism
  • Muscle Cells / pathology
  • Myocardium / metabolism
  • Myocardium / pathology
  • Naphthyridines / chemical synthesis*
  • Naphthyridines / pharmacokinetics
  • Naphthyridines / pharmacology
  • Phosphorylation
  • Piperazines / chemical synthesis*
  • Piperazines / pharmacokinetics
  • Piperazines / pharmacology
  • Protein Binding
  • Protein Kinase C / antagonists & inhibitors*
  • Rats
  • Rats, Inbred Dahl
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship

Substances

  • 2'-cyclohexylamino-6-piperazin-1-yl(2,4')bipyridinyl-4-carboxylic acid amide
  • Aminopyridines
  • Antihypertensive Agents
  • Isoenzymes
  • Naphthyridines
  • Piperazines
  • cyclohexyl-(4-(1-piperazin-1-yl(2,6)naphthyridin-3-yl)pyridin-2-yl)amine
  • 2,2'-Dipyridyl
  • protein kinase D
  • Protein Kinase C
  • Histone Deacetylases