32797-61-8Relevant articles and documents
Protein-Templated Formation of an Inhibitor of the Blood Coagulation Factor Xa through a Background-Free Amidation Reaction
Jaegle, Mike,Steinmetzer, Torsten,Rademann, J?rg
, p. 3718 - 3722 (2017)
Protein-templated reactions enable the target-guided formation of protein ligands from reactive fragments, ideally with no background reaction. Herein, we investigate the templated formation of amides. A nucleophilic fragment that binds to the coagulation factor Xa was incubated with the protein and thirteen differentially activated dipeptides. The protein induced a non-catalytic templated reaction for the phenyl and trifluoroethyl esters; the latter was shown to be a completely background-free reaction. Starting from two fragments with millimolar affinity, a 29 nm superadditive inhibitor of factor Xa was obtained. The fragment ligation reaction was detected with high sensitivity by an enzyme activity assay and by mass spectrometry. The reaction progress and autoinhibition of the templated reaction by the formed ligation product were determined, and the structure of the protein–inhibitor complex was elucidated.
Thrombin inhibitors having a lactam at P3
-
, (2008/06/13)
The present invention provides compounds having a lactam ring at P3 and at P1 have a six-membered heterocyclic ring having two ring nitrogen ring atoms and the remainder of the ring atoms carbon atoms. These compounds have biological activity as active and potent inhibitors of thrombin. Their pharmaceutically acceptable salts, pharmaceutical compositions thereof and methods of using these compounds and pharmaceutical compositions comprising these compounds as therapeutic agents for treatment of disease states in mammals which are characterized by abnormal thrombosis are also described.
Novel, potent non-covalent thrombin inhibitors incorporating P3-lactam scaffolds
Ho, Jonathan Z.,Gibson, Tony S.,Semple
, p. 743 - 748 (2007/10/03)
Evolution of P1-argininal inhibitor prototypes led to a series of non-covalent P3-7-membered lactam inhibitors 1a-w, featuring novel peptidomimetic units that probe each of the S1, S2, and S3 specificity pockets of thrombin. Rigid P1-arginine surrogates possessing a wide range of basicity (calcd pKa's~neutral-14) were surveyed. The design, synthesis, and biological activity of these targets are presented.