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
(-)-(R)-9-(1,2-Dimethoxyethyl)anthracene (8) is successfully employed as a chiral template in the Diels-Alder/retro-Diels-Alder sequence for the preparation of alpha,beta-unsaturated lactams. The cycloadditions proceed with complete diastereoselectivity, and regioselectivity in subsequent transformations of the carbonyl groups is also excellent. Flash vacuum pyrolysis accomplishes the cycloreversion.
ABSTRACT
Clostridium difficile (C. difficile) is a Gram positive, anaerobic bacterium that infects the lumen of the large intestine and produces toxins. This results in a range of syndromes from mild diarrhea to severe toxic megacolon and death. Alarmingly, the prevalence and severity of C. difficile infection are increasing; thus, associated morbidity and mortality rates are rising. 4-Aminothiazolyl analogues of the antibiotic natural product GE2270 A (1) were designed, synthesized, and optimized for the treatment of C. difficile infection. The medicinal chemistry effort focused on enhancing aqueous solubility relative to that of the natural product and previous development candidates (2, 3) and improving antibacterial activity. Structure-activity relationships, cocrystallographic interactions, pharmacokinetics, and efficacy in animal models of infection were characterized. These studies identified a series of dicarboxylic acid derivatives, which enhanced solubility/efficacy profile by several orders of magnitude compared to previously studied compounds and led to the selection of LFF571 (4) as an investigational new drug for treating C. difficile infection.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Clostridioides difficile/drug effects , Enterocolitis, Pseudomembranous/drug therapy , Thiazoles/chemical synthesis , Animals , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/pharmacology , Cricetinae , Crystallography, X-Ray , Enterococcus/drug effects , Escherichia coli Proteins/antagonists & inhibitors , Escherichia coli Proteins/chemistry , Female , Male , Mesocricetus , Mice , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Peptide Elongation Factor Tu/antagonists & inhibitors , Peptide Elongation Factor Tu/chemistry , Rats , Rats, Sprague-Dawley , Solubility , Staphylococcus aureus/drug effects , Streptococcus pyogenes/drug effects , Structure-Activity Relationship , Thiazoles/pharmacokinetics , WaterABSTRACT
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
The development of chiral anthracene templates for use in Diels-Alder/retro Diels-Alder sequences is described. A summary of past results and new progress is reported.