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Bioorg Med Chem Lett ; 28(13): 2256-2260, 2018 07 15.
Article in English | MEDLINE | ID: mdl-29859906

ABSTRACT

Activated thrombin-activatable fibrinolysis inhibitor (TAFIa) is a target molecule for treating thromboembolic disorders. We previously reported that design and synthesis of compound 1 containing a selenol group and chloloaminopyridine. Compound 1 showed high inhibitory activity towards TAFIa, with a high degree of selectivity for TAFIa over carboxypeptidase N (CPN). Here we report investigation of this selectivity. To obtain co-crystal of 1/pp-CPB (a surrogate of TAFIa), we synthesized protected compound 5 as a stabilized precursor of 1. The X-ray crystal structure and docking study indicated that the Cl substituent is accommodated in the pp-CPB specific pocket whereas CPN has no identical pocket. This is important information for the design of drugs targeting TAFIa with high selectivity.


Subject(s)
Aminopyridines/chemistry , Carboxypeptidase B2/antagonists & inhibitors , Organoselenium Compounds/chemistry , Protease Inhibitors/chemistry , Aminopyridines/chemical synthesis , Animals , Binding Sites , Carboxypeptidase B/antagonists & inhibitors , Carboxypeptidase B/chemistry , Humans , Hydrogen Bonding , Lysine Carboxypeptidase/antagonists & inhibitors , Molecular Docking Simulation , Organoselenium Compounds/chemical synthesis , Protease Inhibitors/chemical synthesis , Swine
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