Language
English
Publication Date
9-12-2024
Journal
ACS Medicinal Chemistry Letters Journal
DOI
10.1021/acsmedchemlett.4c00257
PMID
39291021
PMCID
PMC11403753
PubMedCentral® Posted Date
8-5-2024
PubMedCentral® Full Text Version
Post-print
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.
Keywords
kallikrein-related peptidase 3, KLK3, prostate-specific antigen, PSA, structure−activity relationship, small molecule inhibitors
Published Open-Access
yes
Recommended Citation
Erickson, Jeffery A; Jimmidi, Ravikumar; Anamthathmakula, Prashanth; et al., "Synthesis and Optimization of Small Molecule Inhibitors of Prostate Specific Antigen" (2024). Faculty and Staff Publications. 5564.
https://digitalcommons.library.tmc.edu/baylor_docs/5564
Included in
Allergy and Immunology Commons, Biological Phenomena, Cell Phenomena, and Immunity Commons, Pathology Commons