jm100075z_si_001.pdf (157.89 kB)
Identification of Orally Available Naphthyridine Protein Kinase D Inhibitors
journal contribution
posted on 2010-08-12, 00:00 authored by 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. McKinsey, Karl Miranda, Nikos Pagratis, Margaret Pancost, Anup Patnaik, Dillon Phan, Craig Plato, Ming Qian, Vasumathy Rajaraman, Chang Rao, Olga Rozhitskaya, Thomas Ruppen, Jie Shi, Sarah J. Siska, Clayton Springer, Maurice van Eis, Richard B. Vega, Anette von Matt, Lihua Yang, Taeyoung Yoon, Ji-Hu Zhang, Na Zhu, Lauren G. MonovichA 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.
