Citation
Erickson, Jeffery A., Ravikumar Jimmidi, Prashanth Anamthathmakula, Xuan Qin, Jian Wang, Leyi Gong, Jaehyeon Park et al. “Synthesis and Optimization of Small Molecule Inhibitors of Prostate Specific Antigen.” ACS Medicinal Chemistry Letters 15, no. 9 (2024): 1526-1532.
Abstract
Semen liquefaction is a postejaculation process that transforms semen from a gel-like (coagulated) form to a water-like consistency (liquefied). This process is primarily regulated by serine proteases from the prostate gland, most prominently, prostate-specific antigen (PSA; KLK3). Inhibiting PSA activity has the potential to impede liquefaction of human semen, presenting a promising target for nonhormonal contraception in the female reproductive tract. This study employed triazole B1 as a starting compound. Through systematic design, synthesis, and optimization, we identified compound 20 (CDD-3290) as a 216 nM inhibitor of PSA with better stability in media than triazole B1. Further, we also evaluated the selectivity profile of compound 20 (CDD-3290) by testing against closely related proteases and demonstrated excellent inhibition of PSA versus α-chymotrypsin and elastase and similar potency versus thrombin. Thus, compound 20 is an improved PSA inhibitor that can be tested for efficacy in vitro or in the female reproductive tract.
