Hepsin, a type II transmembrane serine protease, is predominantly expressed in prostate cancer (PCa) and plays a crucial role in the promotion of progression and metastasis in PCa. As it is highly up-regulated in PCa over benign prostatic hyperplasia or normal state and its active site is located in the cell surface region, hepsin has emerged as an attractive biomarker for PCa diagnosis and therapy. Previously, Leu-Arg (LR) dipeptides conjugated with ketobenzothiazole (kbt) or ketothiazole ring were reported, exhibiting strong inhibition against hepsin in the nanomolar Ki range. The guanidine group of these analogs was the key moiety for binding to hepsin. However, the cyclized by-products were observed in the synthesis of dipeptide analogs due to the flexibility of side chain in the Arg. With an aim to improve drug-like properties of LR-kbt, cylic ring structures such as phenylguanidine and cyclohexylguanidine were introduced at the side chain of Arg. Novel twelve non-peptidic analogs were prepared in 28% overall yield over 7 steps. Among the final compounds, the phenylguanidine analog (KB734) exhibited hepsin-inhibitory activity in the Ki value of 91 nM and 50-fold hepsin selectivity over matriptase. In silico docking study of KB734 with hepsin demonstrated that the phenylguanidine moiety formed a salt bridge with the carboxylate group of Asp189 similar to the guanidine of Ac-LR-kbt. KB734 has a potential to be used for further structural optimization in the development of novel non-peptidic hepsin inhibitors.

Design and synthesis of non-peptide analogs as novel hepsin inhibitors

2019 Fall National Meeting

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