ABSTRACT
A novel 2,6-naphthyridine was identified by high throughput screen (HTS) as a dual protein kinase C/D (PKC/PKD) inhibitor. PKD inhibition in the heart was proposed as a potential antihypertrophic mechanism with application as a heart failure therapy. As PKC was previously identified as the immediate upstream activator of PKD, PKD vs PKC selectivity was essential to understand the effect of PKD inhibition in models of cardiac hypertrophy and heart failure. The present study describes the modification of the HTS hit to a series of prototype pan-PKD inhibitors with routine 1000-fold PKD vs PKC selectivity. Example compounds inhibited PKD activity in vitro, in cells, and in vivo following oral administration. Their effects on heart morphology and function are discussed herein.
Subject(s)
Aminopyridines/chemical synthesis , Naphthyridines/chemical synthesis , Protein Kinase C/antagonists & inhibitors , Active Transport, Cell Nucleus , Administration, Oral , Aminopyridines/pharmacokinetics , Aminopyridines/pharmacology , Animals , Antihypertensive Agents/chemical synthesis , Antihypertensive Agents/chemistry , Antihypertensive Agents/pharmacology , Blood Pressure/drug effects , Cardiomegaly/drug therapy , 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/pharmacokinetics , Naphthyridines/pharmacology , Phosphorylation , Protein Binding , Rats , Rats, Inbred Dahl , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
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.
