Klein S I, Czekaj M, Gardner C J, Guertin K R, Cheney D L, Spada A P, Bolton S A, Brown K, Colussi D, Heran C L, Morgan S R, Leadley R J, Dunwiddie C T, Perrone M H, Chu V
Department of Cardiovascular Drug Discovery, Collegeville, Pennsylvania 19426, USA.
J Med Chem. 1998 Feb 12;41(4):437-50. doi: 10.1021/jm970482y.
The discovery and some of the basic structure-activity relationships of a series of novel nonpeptide inhibitors of blood coagulation Factor Xa is described. These inhibitors are functionalized beta-alanines, exemplified by 2a. Docking experiments placing 2a in the active site of Factor Xa implied that the most expeditious route to enhancing in vitro potency was to modify the group occupying the S3 site of the enzyme. Increasing the hydrophobic contacts between the inhibitor and the enzyme in this region led to 8, which has served as the prototype for this series. In addition, an enantioselective synthesis of these substituted beta-alanines was also developed.
描述了一系列新型凝血因子Xa非肽抑制剂的发现及其一些基本构效关系。这些抑制剂是功能化的β-丙氨酸，以2a为例。将2a对接至因子Xa活性位点的实验表明，提高体外效力的最快捷途径是修饰占据该酶S3位点的基团。增加该区域抑制剂与酶之间的疏水接触得到了8，它已成为该系列的原型。此外，还开发了这些取代β-丙氨酸的对映选择性合成方法。
