Identification and structure-activity relationship studies of small molecule inhibitors of the human cathepsin D.

Sandeep Goyal, Ketul V Patel, Yadav Nagare, Digambar B Raykar, Santosh S Raikar, Atul Dolas, Princy Khurana, Rajath Cyriac, Sharad Sarak, Mukesh Gangar, Anil K Agarwal, Aditya Kulkarni

Bioorganic & medicinal chemistry 2021 Jan 01

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Cathepsin D, an aspartyl protease, is an attractive therapeutic target for various diseases, primarily cancer and osteoarthritis. However, despite several small molecule cathepsin D inhibitors being developed, that are highly potent, most of them show poor microsomal stability, which in turn limits their clinical translation. Herein, we describe the design, optimization and evaluation of a series of novel non-peptidic acylguanidine based small molecule inhibitors of cathepsin D. Optimization of our hit compound 1a (IC50 = 29 nM) led to the highly potent mono sulphonamide analogue 4b (IC50 = 4 nM), however with poor microsomal stability (HLM: 177 and MLM: 177 μl/min/mg). To further improve the microsomal stability while retaining the potency, we carried out an extensive structure-activity relationship screen which led to the identification of our optimised lead 24e (IC50 = 45 nM), with an improved microsomal stability (HLM: 59.1 and MLM: 86.8 μl/min/mg). Our efforts reveal that 24e could be a good starting point or potential candidate for further preclinical studies against diseases where Cathepsin D plays an important role. Copyright © 2020 Elsevier Ltd. All rights reserved.

Citation

Sandeep Goyal, Ketul V Patel, Yadav Nagare, Digambar B Raykar, Santosh S Raikar, Atul Dolas, Princy Khurana, Rajath Cyriac, Sharad Sarak, Mukesh Gangar, Anil K Agarwal, Aditya Kulkarni. Identification and structure-activity relationship studies of small molecule inhibitors of the human cathepsin D. Bioorganic & medicinal chemistry. 2021 Jan 01;29:115879