Active site-directed plasmin inhibitors: Extension on the P2 residue. Issue 4 (15th February 2016)

• Record Type: Journal Article
• Authors: Hidaka, Koushi; Gohda, Keigo; Teno, Naoki; Wanaka, Keiko; Tsuda, Yuko
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 4(2016)
• Page Start: 545
• Page End: 553
• Publication Date: 2016-02-15
• Subjects: Active site-directed inhibitor -- Plasmin inhibitor -- Selectivity -- Urokinase; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.12.009
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Based on the structure of YO-2 [ N -( trans -4-aminomethylcyclohexanecarbonyl)-l -Tyr( O -picolyl)-NH-octyl], active site-directed plasmin (Plm) inhibitors were explored. The picolyl moiety in the Tyr( O -picolyl) residue (namely, the P2 residue) was replaced with smaller or larger groups, such as hydrogen, tert -butyl, benzyl, (2-naphthyl)methyl, and (quinolin-2-yl)methyl. Those efforts produced compound17 { N -( trans -4-aminomethylcyclohexanecarbonyl)-l -Tyr[ O -(quinolin-2-yl)methyl]-NH-octyl} [IC50 = 0.22 and 77 μM for Plm and urokinase (UK), respectively], which showed not only 2.4-fold greater Plm inhibition than YO-2, but also an improvement in selectivity (Plm/UK) by 35-fold. The docking experiments of the Plm-17 complexes disclosed that the amino group of the tranexamyl moiety interacted with the side-chain of Asp753 which formed S1 site.