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Identification of Orally Available Naphthyridine Protein Kinase D Inhibitors

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Novartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, Massachusetts 02139
Novartis Institutes for BioMedical Research, Basel, Switzerland
§ Gilead Colorado, Inc., 3333 Walnut Street, Boulder, Colorado 80301
*To whom correspondence should be addressed. Phone: 617-871-7606. Fax: 617-871-7045. E-mail: [email protected]
Cite this: J. Med. Chem. 2010, 53, 15, 5400–5421
Publication Date (Web):July 14, 2010
Copyright © 2010 American Chemical Society

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    Abstract Image

    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.

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    Figures S1 and S2 showing the PK iv and po curves for 13c and 13y; Table T1 listing percent activity remaining for kinases. This material is available free of charge via the Internet at

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