- Substituted sulfonic acid N-[(aminoiminomethyl)phenylalkyl]-azaheterocyclylamide compounds
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The compounds of formula I exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. More specifically, they are inhibitors of the activity of Factor Xa. The present invention is directed to compounds of formula I, compositions containing compounds of formula I, and their use, which are for treating a patient suffering from, or subject to, physiological condition which can be ameliorated by the administration of an inhibitor of the activity of Factor Xa.
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- Sulfonamidopyrrolidinone factor Xa inhibitors: Potency and selectivity enhancements via P-1 and P-4 optimization
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Sulfonamidopyrrolidinones were previously disclosed as a selective class of factor Xa (fXa) inhibitors, culminating in the identification of RPR120844 as a potent member with efficacy in vivo. Recognizing the usefulness of the central pyrrolidinone template for the presentation of ligands to the S-1 and S-4 subsites of fXa, studies to optimize the P-1 and P-4 groups were initiated. Sulfonamidopyrrolidinones containing 4-hydroxy- and 4- aminobenzamidines were discovered to be effective inhibitors of fXa. X-ray crystallographic experiments in trypsin and molecular modeling studies suggest that our inhibitors bind by insertion of the 4-hydroxybenzamidine moiety into the S-1 subsite of the fXa active site. Of the P-4 groups examined, the pyridylthienyl sulfonamides were found to confer excellent potency and selectivity especially in combination with 4-hydroxybenzamidine. Compound 20b (RPR130737) was shown to be a potent fXa inhibitor (K1 = 2 nM) with selectivity against structurally related serine proteinases (> 1000 times). Preliminary biological evaluation demonstrates the effectiveness of this inhibitor in common assays of thrombosis in vitro (e.g. activated partial thromboplastin time) and in vivo (e.g. rat FeCl2-induced carotid artery thrombosis model).
- Choi-Sledeski, Yong Mi,McGarry, Daniel G.,Green, Daniel M.,Mason, Helen J.,Becker, Michael R.,Davis, Roderick S.,Ewing, William R.,Dankulich, William P.,Manetta, Vincent E.,Morris, Robert L.,Spada, Alfred P.,Cheney, Daniel L.,Brown, Karen D.,Colussi, Dennis J.,Valeria, Chu,Heran, Christopher L.,Morgan, Suzanne R.,Bentley, Ross G.,Leadley, Robert J.,Maignan, Sebastien,Guilloteau, Jean-Pierre,Dunwiddie, Christopher T.,Pauls, Henry W.
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p. 3572 - 3587
(2007/10/03)
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- SUBSTITUTED SULFONIC ACID N-[(AMINOIMINOMETHYL)PHENYLALKYL]-AZAHETEROCYCLAMIDE COMPOUNDS
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The compounds of formula I exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. More specifically, they are inhibitors of the activity of Factor Xa. The present invention is directed to compounds of formula I, compositions containing compounds of formula I, and their use, which are for treating a patient suffering from, or subject to, physiological condition which can be ameliorated by the administration of an inhibitor of the activity of Factor Xa.
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