Structure- and property-based design of factor Xa inhibitors: pyrrolidin-2-ones with acyclic alanyl amides as P4 motifs.

Autor: Young RJ; GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. Rob.J.Young@gsk.com , Campbell M, Borthwick AD, Brown D, Burns-Kurtis CL, Chan C, Convery MA, Crowe MC, Dayal S, Diallo H, Kelly HA, King NP, Kleanthous S, Mason AM, Mordaunt JE, Patel C, Pateman AJ, Senger S, Shah GP, Smith PW, Watson NS, Weston HE, Zhou P
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2006 Dec 01; Vol. 16 (23), pp. 5953-7. Date of Electronic Publication: 2006 Sep 18.
DOI: 10.1016/j.bmcl.2006.09.001
Abstrakt: 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.
Databáze: MEDLINE
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