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Identification of Orally Available Naphthyridine Protein Kinase D Inhibitors

Meredith, Erik and Ardayfio, Ophelia and Beattie, Kimberley and Dobler, Markus and Enyedy, Istvan and Gaul, Christoph and Hosagrahara, Vinayak and Jewell, Charles and Koch, Keith and Lee, Wendy and Lehmann, Hansjoerg and McKinsey, Timothy and Miranda, Karl and Pagratis, Nikos and Pancost, Margaret and Patnaik, Anup and Plato, Craig and Qian, Ming and Rajaraman, Vasumathy and Rao, Chang and Rozhitskaya, Olga and Ruppen, Thomas and Shi, Jie and Siska, Sarah and Springer, Clayton and Van Eis, Maurice and Vega, Richard and Von Matt, Anette and Yang, Lihua and Yoon, Taeyoung and Zhang, Ji and Zhu, Na and Monovich, Lauren (2010) Identification of Orally Available Naphthyridine Protein Kinase D Inhibitors. Journal of Medicinal Chemistry, 53 (15). pp. 5400-5421. ISSN 0022-2623


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 anti-hypertrophic 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.

Item Type: Article
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Additional Information: archiving not formally supported by this publisher
Keywords: PKD, protein kinase D, cardiac, hypertrophy, HDAC, heart failure
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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16


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