ABSTRACT
Aldosterone is a key signaling component of the renin-angiotensin-aldosterone system and as such has been shown to contribute to cardiovascular pathology such as hypertension and heart failure. Aldosterone synthase (CYP11B2) is responsible for the final three steps of aldosterone synthesis and thus is a viable therapeutic target. A series of imidazole derived inhibitors, including clinical candidate 7n, have been identified through design and structure-activity relationship studies both in vitro and in vivo. Compound 7n was also found to be a potent inhibitor of 11ß-hydroxylase (CYP11B1), which is responsible for cortisol production. Inhibition of CYP11B1 is being evaluated in the clinic for potential treatment of hypercortisol diseases such as Cushing's syndrome.
ABSTRACT
The synthesis and preliminary studies of the SAR of novel 3,5-diarylazole inhibitors of Protein Kinase D (PKD) are reported. Notably, optimized compounds in this class have been found to be active in cellular assays of phosphorylation-dependant HDAC5 nuclear export, orally bioavailable, and highly selective versus a panel of additional putative histone deacetylase (HDAC) kinases. Therefore these compounds could provide attractive tools for the further study of PKD/HDAC5 signaling.
Subject(s)
Azoles/pharmacology , Protein Kinase C/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Administration, Oral , Animals , Azoles/chemical synthesis , Azoles/chemistry , Azoles/pharmacokinetics , Biological Availability , Histone Deacetylases/metabolism , Inhibitory Concentration 50 , Molecular Structure , Protein Kinase C/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Rats , Rats, Sprague-Dawley , Signal Transduction , 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.
Subject(s)
2,2'-Dipyridyl/analogs & derivatives , Aminopyridines/chemical synthesis , Naphthyridines/chemical synthesis , Piperazines/chemical synthesis , Protein Kinase C/antagonists & inhibitors , 2,2'-Dipyridyl/chemical synthesis , 2,2'-Dipyridyl/pharmacokinetics , 2,2'-Dipyridyl/pharmacology , Active Transport, Cell Nucleus , Administration, Oral , 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/pharmacokinetics , Naphthyridines/pharmacology , Phosphorylation , Piperazines/pharmacokinetics , Piperazines/pharmacology , Protein Binding , Rats , Rats, Inbred Dahl , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Histone deacetylase 5 (HDAC5) represses expression of nuclear genes that promote cardiac hypertrophy. Agonism of a variety of G protein coupled receptors (GPCRs) triggers phosphorylation-dependent nuclear export of HDAC5 via the CRM1 nuclear export receptor, resulting in derepression of pro-hypertrophic genes. A cell-based high-throughput screen of a commercial compound collection was employed to identify compounds with the ability to preserve the nuclear fraction of GFP-HDAC5 in primary cardiomyocytes exposed to GPCR agonists. A hit compound potently inhibited agonist-induced GFP-HDAC5 nuclear export in cultured neonatal rat ventricular myocytes (NRVMs). A small set of related compounds was designed and synthesized to evaluate structure-activity relationship (SAR). The results demonstrated that inhibition of HDAC5 nuclear export was a result of compounds irreversibly reacting with a key cysteine residue in CRM1 that is required for its function. CRM1 inhibition by the compounds also resulted in potent suppression of cardiomyocyte hypertrophy. These studies define a novel class of anti-hypertrophic compounds that function through irreversible inhibition of CRM1-dependent nuclear export.
