ItemArticle

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

Title
Identification and structure-activity relationship studies of small molecule inhibitors of the human cathepsin D
Creator
Goyal S.; Patel K.V.; Nagare Y.; Raykar D.B.; Raikar S.S.; Dolas A.; Khurana P.; Cyriac R.; Sarak S.; Gangar M.; Agarwal A.K.; Kulkarni A.
Description
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 ?l/min/mg). To further improve the microsomal stability while retaining the potency, we carried out an extensive structureactivity 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 ?l/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. 2020 Elsevier Ltd
Source
Bioorganic and Medicinal Chemistry, Vol-29
Date
2021-01-01
Publisher
Elsevier Ltd
Subject
Cathepsin D
Coverage
Goyal S., Aten Porus Lifesciences, Bangalore, 560068, India; Patel K.V., Aten Porus Lifesciences, Bangalore, 560068, India; Nagare Y., Aten Porus Lifesciences, Bangalore, 560068, India; Raykar D.B., Aten Porus Lifesciences, Bangalore, 560068, India; Raikar S.S., Aten Porus Lifesciences, Bangalore, 560068, India; Dolas A., Aten Porus Lifesciences, Bangalore, 560068, India; Khurana P., Aten Porus Lifesciences, Bangalore, 560068, India; Cyriac R., Aten Porus Lifesciences, Bangalore, 560068, India; Sarak S., Aten Porus Lifesciences, Bangalore, 560068, India; Gangar M., Aten Porus Lifesciences, Bangalore, 560068, India; Agarwal A.K., Department of Chemistry, CHRIST (Deemed to be University), Bengaluru, Karnataka, India; Kulkarni A., Aten Porus Lifesciences, Bangalore, 560068, India, Avaliv Therapeutics, Naples, FL, United States
Rights
Restricted Access
Relation
ISSN: 9680896; PubMed ID: 33271453; CODEN: BMECE
Format
Online
Language
English
Type
Article

Collection

Articles

Citation

Goyal S.; Patel K.V.; Nagare Y.; Raykar D.B.; Raikar S.S.; Dolas A.; Khurana P.; Cyriac R.; Sarak S.; Gangar M.; Agarwal A.K.; Kulkarni A., “Identification and structure-activity relationship studies of small molecule inhibitors of the human cathepsin D,” CHRIST (Deemed To Be University) Institutional Repository, accessed February 25, 2025, https://archives.christuniversity.in/items/show/16099.

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