Design and Optimization of Selective Protein Kinase C 胃 (PKC胃) Inhibitors for the Treatment of Autoimmune Diseases

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• 作者：Juan-Miguel Jimenez ; Dean Boyall ; Guy Brenchley ; Philip N. Collier ; Christopher J. Davis ; Damien Fraysse ; Shazia B. Keily ; Jaclyn Henderson ; Andrew Miller ; Francoise Pierard ; Luca Settimo ; Heather C. Twin ; Claire M. Bolton ; Adam P. Curnock ; Peter Chiu ; Adam J. Tanner ; Stephen Young
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：March 14, 2013
• 年：2013
• 卷：56
• 期：5
• 页码：1799-1810
• 全文大小：460K
• 年卷期：v.56,no.5(March 14, 2013)
• ISSN：1520-4804

文摘

Protein kinase C 胃 (PKC胃) has a central role in T cell activation and survival; however, the dependency of T cell responses to the inhibition of this enzyme appears to be dictated by the nature of the antigen and by the inflammatory environment. Studies in PKC胃-deficient mice have demonstrated that while antiviral responses are PKC胃-independent, T cell responses associated with autoimmune diseases are PKC胃-dependent. Thus, potent and selective inhibition of PKC胃 is expected to block autoimmune T cell responses without compromising antiviral immunity. Herein, we describe the development of potent and selective PKC胃 inhibitors, which show exceptional potency in cells and in vivo. By use of a structure based rational design approach, a 1000-fold improvement in potency and 76-fold improvement in selectivity over closely related PKC isoforms such as PKC未 were obtained from the initial HTS hit, together with a big improvement in lipophilic efficiency (LiPE).