Design and construction of novel thrombin inhibitors featuring P3-P4 quaternary lactam dipeptide surrogates.
Potent serine protease inhibitor 1a featuring a hybrid P3-P4 quaternary lactam dipeptide surrogate was prepared based upon SAR and molecular modeling investigations and in order to further probe the S2/S3 thrombin and FXa subsites. An efficient and concise synthetic route to the key aminolactam intermediate 4 was developed. The design, synthesis, and biological activity of this target and its P3-P4 diastereomer 1b is presented.
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Department of Medicinal Chemistry, Corvas International, Inc., San Diego, CA 92121, USA.
D002851:Chromatography, High Pressure Liquid; D004151:Dipeptides / Q000737:chemistry; D006146:Guanidines / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007769:Lactams / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D010880:Piperidines / Q000737:chemistry* / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors*
C114376:CVS 1578; C116772:CVS 1897; D004151:Dipeptides; D006146:Guanidines; D007769:Lactams; D010880:Piperidines; D015842:Serine Proteinase Inhibitors; D013917:Thrombin