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

Abstract

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.

• Authors: 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
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 29 Pg. 115879 (01 01 2021) ISSN: 1464-3391 [Electronic] England
• PMID: 33271453 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Ltd. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Small Molecule Libraries
• CTSD protein, human
• Cathepsin D

Topics

• Cathepsin D (antagonists & inhibitors, metabolism)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Humans
• Microsomes, Liver (chemistry, metabolism)
• Molecular Structure
• Small Molecule Libraries (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship