Kohrt Jeffrey T, Filipski Kevin J, Cody Wayne L, Bigge Christopher F, La Frances, Welch Kathleen, Dahring Tawny, Bryant John W, Leonard Daniele, Bolton Gary, Narasimhan Lakshmi, Zhang Erli, Peterson J Thomas, Haarer Staci, Sahasrabudhe Vaishali, Janiczek Nancy, Desiraju Shrilakshmi, Hena Mostofa, Fiakpui Charles, Saraswat Neerja, Sharma Raman, Sun Shaoyi, Maiti Samarendra N, Leadley Robert, Edmunds Jeremy J
Pfizer Global Research and Development, Michigan Labs, Ann Arbor, 48105, USA.
Bioorg Med Chem. 2006 Jul 1;14(13):4379-92. doi: 10.1016/j.bmc.2006.02.040. Epub 2006 Mar 10.
Herein, we report on the identification of three potent glycine and related amino acid-based series of FXa inhibitors containing a neutral P1 chlorophenyl pharmacophore. A X-ray crystal structure has shown that constrained glycine derivatives with optimized N-substitution can greatly increase hydrophobic interactions in the FXa active site. Also, the substitution of a pyridone ring for a phenylsulfone ring in the P4 sidechain resulted in an inhibitor with enhanced oral bioavailability.
在此，我们报告了三种基于甘氨酸及相关氨基酸的强效FXa抑制剂系列的鉴定结果，这些系列含有中性P1氯苯基药效基团。X射线晶体结构表明，具有优化N-取代的受限甘氨酸衍生物可大大增加FXa活性位点中的疏水相互作用。此外，在P4侧链中用吡啶酮环取代苯砜环产生了一种具有更高口服生物利用度的抑制剂。
