基于结构和性质的凝血因子Xa抑制剂设计：以无环丙氨酰酰胺为P4基序的吡咯烷-2-酮类化合物
Structure- and property-based design of factor Xa inhibitors: pyrrolidin-2-ones with acyclic alanyl amides as P4 motifs.
作者信息
Young Robert J, Campbell Matthew, Borthwick Alan D, Brown David, Burns-Kurtis Cynthia L, Chan Chuen, Convery Máire A, Crowe Miriam C, Dayal Satish, Diallo Hawa, Kelly Henry A, King N Paul, Kleanthous Savvas, Mason Andrew M, Mordaunt Jackie E, Patel Champa, Pateman Anthony J, Senger Stefan, Shah Gita P, Smith Paul W, Watson Nigel S, Weston Helen E, Zhou Ping
机构信息
GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
出版信息
Bioorg Med Chem Lett. 2006 Dec 1;16(23):5953-7. doi: 10.1016/j.bmcl.2006.09.001. Epub 2006 Sep 18.
Structure-based drug design was exploited in the synthesis of 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group with acyclic tertiary amide termini. Optimized hydrophobic contacts of one amide substituent in P4 were complemented by hydrophobicity-modulating features in the second, producing potent fXa inhibitors including examples with excellent anticoagulant properties.
基于结构的药物设计被用于合成基于3-(6-氯萘-2-基磺酰基)氨基吡咯烷-2-酮的凝血因子Xa（fXa）抑制剂，该抑制剂引入了具有无环叔酰胺末端的丙氨酰胺P4基团。P4中一个酰胺取代基的优化疏水接触由第二个取代基中的疏水性调节特征补充，从而产生了强效的fXa抑制剂，包括具有优异抗凝特性的实例。
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