Evaluation of Quinazoline Analogues as Glucocerebrosidase Inhibitors with Chaperone Activity

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• 作者：Juan J. Marugan ; Wei Zheng ; Omid Motabar ; Noel Southall ; Ehud Goldin ; Wendy Westbroek ; Barbara K. Stubblefield ; Ellen Sidransky ; Ronald A. Aungst ; Wendy A. Lea ; Anton Simeonov ; William Leister ; Christopher P. Austin
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：February 24, 2011
• 年：2011
• 卷：54
• 期：4
• 页码：1033-1058
• 全文大小：1765K
• 年卷期：v.54,no.4(February 24, 2011)
• ISSN：1520-4804

文摘

Gaucher disease is a lysosomal storage disorder (LSD) caused by deficiency in the enzyme glucocerebrosidase (GC). Small molecule chaperones of protein folding and translocation have been proposed as a promising therapeutic approach to this LSD. Most small molecule chaperones described in the literature contain an iminosugar scaffold. Here we present the discovery and evaluation of a new series of GC inhibitors with a quinazoline core. We demonstrate that this series can improve the translocation of GC to the lysosome in patient-derived cells. To optimize this chemical series, systematic synthetic modifications were performed and the SAR was evaluated and compared using three different readouts of compound activity: enzymatic inhibition, enzyme thermostabilization, and lysosomal translocation of GC.