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Your search keyword '"Monovich, Lauren G."' showing total 2 results
Start Over Author "Monovich, Lauren G." Topic protein kinase c
2 results on '"Monovich, Lauren G."'

1. Identification of potent and selective amidobipyridyl inhibitors of protein kinase D.

Author

Meredith EL, Beattie K, Burgis R, Capparelli M, Chapo J, Dipietro L, Gamber G, Enyedy I, Hood DB, Hosagrahara V, Jewell C, Koch KA, Lee W, Lemon DD, McKinsey TA, Miranda K, Pagratis N, Phan D, Plato C, Rao C, Rozhitskaya O, Soldermann N, Springer C, van Eis M, Vega RB, Yan W, Zhu Q, and Monovich LG

Subjects
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 Relationship, 2,2'-Dipyridyl analogs & derivatives, Aminopyridines chemical synthesis, Naphthyridines chemical synthesis, Piperazines chemical synthesis, Protein Kinase C antagonists & inhibitors
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.

Published
2010
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2. Identification of orally available naphthyridine protein kinase D inhibitors.

Author

Meredith EL, Ardayfio O, Beattie K, Dobler MR, Enyedy I, Gaul C, Hosagrahara V, Jewell C, Koch K, Lee W, Lehmann H, McKinsey TA, Miranda K, Pagratis N, Pancost M, Patnaik A, Phan D, Plato C, Qian M, Rajaraman V, Rao C, Rozhitskaya O, Ruppen T, Shi J, Siska SJ, Springer C, van Eis M, Vega RB, von Matt A, Yang L, Yoon T, Zhang JH, Zhu N, and Monovich LG

Subjects
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 Relationship, Aminopyridines chemical synthesis, Naphthyridines chemical synthesis, Protein Kinase C antagonists & inhibitors
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.

Published
2010
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