Identification of Orally Available Naphthyridine Protein Kinase D Inhibitors
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- 作者：Erik L. Meredith ; Ophelia Ardayfio ; Kimberly Beattie ; Markus R. Dobler ; Istvan Enyedy ; Christoph Gaul ; Vinayak Hosagrahara ; Charles Jewell ; Keith Koch ; Wendy Lee ; HansJoerg Lehmann ; Timothy A. McKinse
- 刊名：Journal of Medicinal Chemistry
- 出版年：2010
- 出版时间：August 12, 2010
- 年：2010
- 卷：53
- 期：15
- 页码：5400-5421
- 全文大小：1405K
- 年卷期：v.53,no.15(August 12, 2010)
- ISSN：1520-4804
文摘
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.