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Structure- and property-based design of factor Xa inhibitors: pyrrolidin-2-ones with acyclic alanyl amides as P4 motifs |
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| Authors: | 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 |
| Institution: | GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. Rob.J.Young@gsk.com |
| Abstract: | 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. |
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