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

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.