- Improving the Selectivity of PACE4 Inhibitors through Modifications of the P1 Residue
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Paired basic amino acid cleaving enzyme 4 (PACE4), a serine endoprotease of the proprotein convertases family, has been recognized as a promising target for prostate cancer. We previously reported a selective and potent peptide-based inhibitor for PACE4, named the multi-Leu peptide (Ac-LLLLRVKR-NH2 sequence), which was then modified into a more potent and stable compound named C23 with the following structure: Ac-dLeu-LLLRVK-Amba (Amba: 4-amidinobenzylamide). Despite improvements in both in vitro and in vivo profiles of C23, its selectivity for PACE4 over furin was significantly reduced. We examined other Arg-mimetics instead of Amba to regain the lost selectivity. Our results indicated that the replacement of Amba with 5-(aminomethyl)picolinimidamide increased affinity for PACE4 and restored selectivity. Our results also provide a better insight on how structural differences between S1 pockets of PACE4 and furin could be employed in the rational design of selective inhibitors.
- Dianati, Vahid,Navals, Pauline,Couture, Frédéric,Desjardins, Roxane,Dame, Anthony,Kwiatkowska, Anna,Day, Robert,Dory, Yves L.
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p. 11250 - 11260
(2019/01/04)
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- Thrombin inhibitors, the preparation and use thereof
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Compounds of the formula and the salts thereof with physiologically tolerated acids and the stereoisomers thereof, in which the substituents have the meanings stated in the description, are described. Also disclosed are intermediates for their preparation. The compounds are suitable for controlling diseases.
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- Noncovalent tripeptidic thrombin inhibitors incorporating amidrazone, amine and amidine functions at P1
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A series of noncovalent tripeptidic thrombin inhibitors incorporating amidrazone, amine and amidine functions at P1 was investigated. While the amidrazone and the amine series displayed limited oral absorption, the amidine series demonstrated generally good oral absorption and strong antithrombotic activity; the single-digit picomolar Ki achieved from this series is among the best yet reported. The present work highlights the benzamidine compound 11f (LB30812) that exhibits excellent overall profiles of potency, oral absorption and antithrombotic efficacy.
- Lee, Koo,Jung, Won-Hyuk,Park, Cheol Won,Park, Hee Dong,Lee, Sun Hwa,Kwon, O Hwan
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p. 1017 - 1022
(2007/10/03)
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- Thrombin inhibitors
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Thrombin inhibitors of the formula STR1 where R 1, A, B and D have the meaning indicated in the description, and intermediates for the preparation thereof are described.The compounds I are suitable for controlling diseases.
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