Discovery of a Novel Series of Imidazo[1,2-a]pyrimidine Derivatives as Potent and Orally Bioavailable Lipoprotein-Associated Phospholipase A2 Inhibitors

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• 作者：Xinde Chen ; Wenwei Xu ; Kai Wang ; Mingguang Mo ; Wei Zhang ; Lili Du ; Xiaojing Yuan ; Yechun Xu ; Yiping Wang ; Jianhua Shen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：November 12, 2015
• 年：2015
• 卷：58
• 期：21
• 页码：8529-8541
• 全文大小：565K
• ISSN：1520-4804

文摘

Inhibition of lipoprotein-associated phospholipase A₂ (Lp-PLA₂) has been suggested to be a promising therapeutic strategy for several inflammation-associated diseases, including atherosclerosis, Alzheimer鈥檚 disease, and diabetic macular edema. Herein, we report the discovery of a novel series of Lp-PLA₂ inhibitors constructed on an imidazo[1,2-a]pyrimidine scaffold through a conformational restriction strategy. Structure鈥揳ctivity relationship (SAR) analysis resulted in the identification of several compounds with high potency in vitro and good metabolic stability in liver S9 fractions. Compounds 7c and 14b selected for further exploration in vivo demonstrated excellent pharmacokinetic profiles and exhibited significant inhibitory efficacy in SD rats upon oral dosing.