Active site-directed plasmin inhibitors: Extension on the P2 residue.
Bioorg Med Chem
; 24(4): 545-53, 2016 Feb 15.
Article
em En
| MEDLINE
| ID: mdl-26732532
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 compound 17 {N-(trans-4-aminomethylcyclohexanecarbonyl)-l-Tyr[O-(quinolin-2-yl)methyl]-NH-octyl} [IC50=0.22 and 77µM 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.
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Base de dados:
MEDLINE
Assunto principal:
Fibrinolisina
/
Antifibrinolíticos
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article