- Discovery of potent, efficacious, and orally bioavailable inhibitors of blood coagulation factor Xa with neutral P1 moieties
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The bicyclic dihydropyrazolopyridinone scaffold allowed for incorporation of multiple P1 moieties with subnanomolar binding affinities for blood coagulation factor Xa. The compound 3-[6-(2′-dimethylaminomethyl-biphenyl-4-yl)-7-oxo-3-trifluoro-methyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridine-l-yl]-benzamide 6d shows good fXa potency, selectivity, in vivo efficacy and oral bioavailability. Compound 6d was selected for further pre-clinical evaluations.
- Pinto, Donald J.P.,Galemmo Jr., Robert A.,Quan, Mimi L.,Orwat, Michael J.,Clark, Charles,Li, Renhua,Wells, Brian,Woerner, Francis,Alexander, Richard S.,Rossi, Karen A.,Smallwood, Angela,Wong, Pancras C.,Luettgen, Joseph M.,Rendina, Alan R.,Knabb, Robert M.,He, Kan,Wexler, Ruth R.,Lam, Patrick Y.S.
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p. 5584 - 5589
(2007/10/03)
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- Carbonic anhydrase inhibitors: Synthesis and inhibition of cytosolic/membrane-associated carbonic anhydrase isozymes I, II, and IX with sulfonamides incorporating hydrazino moieties
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Targeting proteins overexpressed in hypoxic tumors is as an important means of controlling cancer disease. One such protein is the carbonic anhydrase (CA) isoenzyme IX, which in some types of tumors is overexpressed 150-200-fold. We report here a series of sulfonamide derivatives, prepared from 2-carbohydrazido- and 4-carbohydrazido-benzenesulfonamides, which were further derivatized by reaction with aryl isocyanates or arylsulfonyl isocyanates. Several low nanomolar CA IX inhibitors were detected in this way. SAR is discussed for the diverse types of inhibitors and their affinity for different isozymes, with the aim of obtaining isozyme-specific CA IX inhibitors, with putative applications as antitumor drugs.
- Winum, Jean-Yves,Dogné, Jean-Michel,Casini, Angela,De Leval, Xavier,Montero, Jean-Louis,Scozzafava, Andrea,Vullo, Daniela,Innocenti, Alessio,Supuran, Claudiu T.
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p. 2121 - 2125
(2007/10/03)
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