Synthesis and Optimization of Small Molecule Inhibitors of Prostate Specific Antigen

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2024-08-05 DOI:10.1021/acsmedchemlett.4c0025710.1021/acsmedchemlett.4c00257

Jeffery A. Erickson, Ravikumar Jimmidi, Prashanth Anamthathmakula, Xuan Qin, Jian Wang, Leyi Gong, Jaehyeon Park, Gary Koolpe, Caitlin Tan, Martin M. Matzuk, Feng Li, Srinivas Chamakuri* and Wipawee Winuthayanon*,

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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.

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前列腺特异性抗原小分子抑制剂的合成与优化

精液液化是射精后的一个过程，它将精液从凝胶状（凝固）转变为水样稠度（液化）。这一过程主要由前列腺中的丝氨酸蛋白酶调控，其中最主要的是前列腺特异性抗原（PSA；KLK3）。抑制 PSA 的活性有可能阻碍人类精液的液化，从而为女性生殖道的非激素避孕提供了一个很有前景的靶点。本研究采用三唑 B1 作为起始化合物。通过系统设计、合成和优化，我们发现化合物 20（CDD-3290）是一种 216 nM 的 PSA 抑制剂，在介质中的稳定性优于三唑 B1。此外，我们还通过对密切相关的蛋白酶进行测试，评估了化合物 20 (CDD-3290) 的选择性特征，结果表明它对α-糜蛋白酶和弹性蛋白酶具有极佳的抑制作用，对凝血酶也具有类似的效力。因此，化合物 20 是一种经过改进的 PSA 抑制剂，可以在体外或女性生殖道中进行药效测试。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.