Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
J Med Chem. 2010 Aug 12;53(15):5400-21. doi: 10.1021/jm100075z.
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.
一种新型的 2,6-萘啶被高通量筛选（HTS）鉴定为双重蛋白激酶 C/D（PKC/PKD）抑制剂。PKD 抑制作用被认为是一种潜在的抗肥厚机制，可应用于心力衰竭治疗。由于 PKC 先前被鉴定为 PKD 的直接上游激活剂，因此 PKD 与 PKC 的选择性对于理解 PKD 抑制在心肌肥厚和心力衰竭模型中的作用至关重要。本研究描述了对 HTS 命中化合物的修饰，得到了一系列常规的、具有 1000 倍 PKD 与 PKC 选择性的泛 PKD 抑制剂原型。实例化合物在体外、细胞内和口服给药后均可抑制 PKD 的活性。本文讨论了它们对心脏形态和功能的影响。
