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Identification of orally available naphthyridine protein kinase D inhibitors

Meredith, Erik L ; Ardayfio, Ophelia ; Beattie, Kimberly ; Dobler, Markus R ; Enyedy, Istvan ; Gaul, Christoph ; Hosagrahara, Vinayak ; Jewell, Charles ; Koch, Keith ; Lee, Wendy ; Lehmann, Hansjoerg ; Mckinsey, Timothy A ; Miranda, Karl ; Pagratis, Nikos ; Pancost, Margaret ; Patnaik, Anup ; Phan, Dillon ; Plato, Craig ; Qian, Ming ; Rajaraman, Vasumathy ; Rao, Chang ; Rozhitskaya, Olga ; Ruppen, Thomas ; Shi, Jie ; Siska, Sarah J ; Springer, Clayton ; Van Eis, Maurice ; Vega, Richard B ; Von Matt, Anette ; Yang, Lihua ; Yoon, Taeyoung ; Zhang, Ji-Hu ; Zhu, Na ; Monovich, Lauren G

Journal of medicinal chemistry, 12 August 2010, Vol.53(15), pp.5400-21 [Peer Reviewed Journal]

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Title:
Identification of orally available naphthyridine protein kinase D inhibitors
Author: Meredith, Erik L ; Ardayfio, Ophelia ; Beattie, Kimberly ; Dobler, Markus R ; Enyedy, Istvan ; Gaul, Christoph ; Hosagrahara, Vinayak ; Jewell, Charles ; Koch, Keith ; Lee, Wendy ; Lehmann, Hansjoerg ; Mckinsey, Timothy A ; Miranda, Karl ; Pagratis, Nikos ; Pancost, Margaret ; Patnaik, Anup ; Phan, Dillon ; Plato, Craig ; Qian, Ming ; Rajaraman, Vasumathy ; Rao, Chang ; Rozhitskaya, Olga ; Ruppen, Thomas ; Shi, Jie ; Siska, Sarah J ; Springer, Clayton ; Van Eis, Maurice ; Vega, Richard B ; Von Matt, Anette ; Yang, Lihua ; Yoon, Taeyoung ; Zhang, Ji-Hu ; Zhu, Na ; Monovich, Lauren G
Description: 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.
Is Part Of: Journal of medicinal chemistry, 12 August 2010, Vol.53(15), pp.5400-21
Identifier: E-ISSN: 1520-4804 ; PMID: 20684591 Version:1 ; DOI: 10.1021/jm100075z
Subjects: Aminopyridines -- Chemical Synthesis ; Naphthyridines -- Chemical Synthesis ; Protein Kinase C -- Antagonists & Inhibitors
Language: English
Source: MEDLINE/PubMed (U.S. National Library of Medicine)

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Identification of orally available naphthyridine protein kinase D inhibitors

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