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 Eis, Maurice van Vega, Richard B. Matt, Anette von Yang, Lihua Yoon, Taeyoung Zhang, Ji-Hu Zhu, Na Monovich, Lauren G. Identification of Orally Available Naphthyridine Protein Kinase D Inhibitors 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. PKD inhibition;PKD vs PKC selectivity;heart failure therapy;HTS 2010-08-12
    https://acs.figshare.com/articles/journal_contribution/Identification_of_Orally_Available_Naphthyridine_Protein_Kinase_D_Inhibitors/2743147
10.1021/jm100075z.s001