- Phenylimidazoles as potent and selective inhibitors of coagulation factor XIa with in vivo antithrombotic activity
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Novel inhibitors of FXIa containing an (S)-2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethanamine core have been optimized to provide compound 16b, a potent, reversible inhibitor of FXIa (Ki = 0.3 nM) having in vivo antithrombotic efficacy in the rabbit AV-shunt thrombosis model (ID50 = 0.6 mg/kg + 1 mg kg-1 h-1). Initial analog selection was informed by molecular modeling using compounds 11a and 11h overlaid onto the X-ray crystal structure of tetrahydroquinoline 3 complexed to FXIa. Further optimization was achieved by specific modifications derived from careful analysis of the X-ray crystal structure of the FXIa/11h complex. Compound 16b was well tolerated and enabled extensive pharmacologic evaluation of the FXIa mechanism up to the ID90 for thrombus inhibition.
- Hangeland, Jon J.,Friends, Todd J.,Rossi, Karen A.,Smallheer, Joanne M.,Wang, Cailan,Sun, Zhong,Corte, James R.,Fang, Tianan,Wong, Pancras C.,Rendina, Alan R.,Barbera, Frank A.,Bozarth, Jeffrey M.,Luettgen, Joseph M.,Watson, Carol A.,Zhang, Ge,Wei, Anzhi,Ramamurthy, Vidhyashankar,Morin, Paul E.,Bisacchi, Gregory S.,Subramaniam, Srinath,Arunachalam, Piramanayagam,Mathur, Arvind,Seiffert, Dietmar A.,Wexler, Ruth R.,Quan, Mimi L.
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p. 9915 - 9932
(2015/02/05)
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- ARYLPROPIONAMIDE, ARYLACRYLAMIDE, ARYLPROPYNAMIDE, OR ARYLMETHYLUREA ANALOGS AS FACTOR XIA INHIBITORS
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The present invention provides compounds of Formula (I): Formula (I) or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate form thereof, wherein the variables A, L1, M and R11 are as defined herein. The compounds of Formula (I) are selective inhibitors of serine protease enzymes of the coagulation cascade and/or contact activation system; for example thrombin, factor Xa, factor XIa, factor IXa, factor VIIa and/or plasma kallikrein. In particular, it relates to compounds that are selective factor XIa inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and/or inflammatory disorders using the same.
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Page/Page column 121
(2008/06/13)
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- HETEROCYCLIC CARBONYL COMPOUNDS
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The invention relates to novel heterocyclic compounds of formula (I) wherein R1, D, W, T and T' have the meaning cited in the claim 1. Said compounds are SGK-inhibitors and can be used in the treatment of SGK-related diseases and disorders such as diabetes, obesity, metabolic syndrome (dyslipidemia), systemic and pulmonal hypertension, cardiovascular diseases and renal diseases, and generally for any kind of fibroses and inflammatory processes.
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Page/Page column 59-60
(2008/06/13)
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- 3-AMINOINDAZOLES
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Novel 3-aminoindazoles of formula (I) are SGK-inhibitors and can be used for treating SGK-related diseases and illnesses such as diabetes, obesity, metabolic syndrome (dyslipidaemia), systemic and pulmonary hypertonia, cardiovascular diseases and renal diseases, and generally any type of fibroses and inflammatory processes.
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Page/Page column 68
(2008/06/13)
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- FIVE-MEMBERED HETEROCYCLES USEFUL AS SERINE PROTEASE INHIBITORS
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The present invention provides a method for treating a thrombotic or an inflammatory disorder administering to a patient in need thereof a therapeutically effective amount of at least one compound of Formula (I) or Formula (V): (I) [INSERTCHEMICAL STRUCTURE HERE] (V)[INSERT CHEMICAL STRUCTURE HERE] or a stereoisomer or pharmaceutically acceptable salt or solvate form thereof, wherein the variables A, L, Z, R3, R4, R6, R11, X1, X2, and X3 are as defined herein. The compounds of Formula (I) are useful as selective inhibitors of serine protease enzymes of the coagulation cascade and/or contact activation system; for example thrombin, factor Xa, factor XIa, factor IXa, factor VIIa and/or plasma kallikrein. In particular, it relates to compounds that are selective factor XIa inhibitors. This invention also provides compounds within the scope of Formula I and relates to pharmaceutical compositions comprising these compounds.
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Page/Page column 153
(2008/06/13)
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- Application of aryloximes as solid-phase ketone linkers.
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In both solution and the solid phase, a variety of ketone oxime anions have been treated with 4-substituted-2-fluorobenzonitriles to give the corresponding nucleophilic aromatic substitution aryloxime adducts. Under aqueous acidic conditions, these adducts underwent cyclization to give the corresponding ketones. Suzuki and amide coupling reactions were also successfully performed on two resin-bound oximes followed by subsequent cyclorelease to give ketone product in good yields and purities. [reaction--see text]
- Lepore, Salvatore D,Wiley, Michael R
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