Structural highlights
Publication Abstract from PubMed
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.
Structural basis for the selective inhibition of activated thrombin-activatable fibrinolysis inhibitor (TAFIa) by a selenium-containing inhibitor with chloro-aminopyridine as a basic group.,Itoh T, Yoshimoto N, Hirano Y, Yamamoto K Bioorg Med Chem Lett. 2018 Jul 15;28(13):2256-2260. doi:, 10.1016/j.bmcl.2018.05.042. Epub 2018 May 23. PMID:29859906[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Itoh T, Yoshimoto N, Hirano Y, Yamamoto K. Structural basis for the selective inhibition of activated thrombin-activatable fibrinolysis inhibitor (TAFIa) by a selenium-containing inhibitor with chloro-aminopyridine as a basic group. Bioorg Med Chem Lett. 2018 Jul 15;28(13):2256-2260. doi:, 10.1016/j.bmcl.2018.05.042. Epub 2018 May 23. PMID:29859906 doi:http://dx.doi.org/10.1016/j.bmcl.2018.05.042