677326-82-8Relevant articles and documents
Development and characterization of biphenylsulfonamides as novel inhibitors of bone resorption
Greig, Iain R.,Idris, Aymen I.,Ralston, Stuart H.,Van't Hof, Rob J.
, p. 7487 - 7492 (2007/10/03)
Increased osteoclastic bone resorption plays a central role in the pathogenesis of many bone diseases, and osteoclast inhibitors are the most widely used treatments for these diseases. We have identified and characterized a series of novel biphenylsulfona
ARYL ALKYL SULFONAMIDES AS THERAPEUTIC AGENTS FOR THE TREATMENT OF BONE CONDITIONS
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Page/Page column 103, (2008/06/13)
The present invention pertains to certain aryl alkyl sulfonamides and derivatives thereof which, inter alia, inhibit osteoclast survival, formation, and/or activity; and/or inhibit bone resorption, and more particularly to compounds of the formula: [Inser
Structure-activity relationships and pharmacokinetic analysis for a series of potent, systemically available biphenylsulfonamide matrix metalloproteinase inhibitors
O'Brien, Patrick M.,Ortwine, Daniel F.,Pavlovsky, Alexander G.,Picard, Joseph A.,Sliskovic, Drago R.,Roth, Bruce D.,Dyer, Richard D.,Johnson, Linda L.,Man, Chiu Fai,Hallak, Hussein
, p. 156 - 166 (2007/10/03)
A series of biphenylsulfonamide derivatives of (S)-2-(biphenyl-4- sulfonylamino)-3-methylbutyric acid (5) were prepared and evaluated for their ability to inhibit matrix metalloproteinases (MMPs). For this series of compounds, our objective was to systematically replace substituents appended to the biphenyl and α-position of 5 with structurally diverse functionalities to assess the effects these changes have on biological and pharmacokinetic activity. The ensuing structure-activity relationship (SAR) studies showed that biphenylsulfonamides substituted with bromine in the 4'- position (11c) significantly improved in vitro activity and exhibited superior pharmacokinetics (C(max), t(1/2), AUCs), relative to compound 5. Varying the lipophilicity of the α-position by replacing the isopropyl group of 11c with a variety of substituents, in general, maintained potency versus MMP-2, -3, and -13 but decreased the oral systemic availability. Subsequent evaluation of its enantiomer, 11c', showed that both compounds were equally effective MMP inhibitors. In contrast, the corresponding hydroxamic acid enantiomeric pair, 16a (S-isomer) and 16a' (R-isomer), stereoselectivity inhibited MMPs. For the first time in this series, 16a' provided nanomolar potency against MMP-1, -7, and -9 (IC50'S = 110, 140, and 18 nM, respectively), whereas 16a was less potent against these MMPs (IC(50)'S = 24, 78, and 84 μM, respectively). However, unlike 11c, compound 16a' afforded very low plasma concentrations following a single 5 mg/kg oral dose in rat. Subsequent X-ray crystal structures of the catalytic domain of stromelysin (MMP-3CD) complexed with inhibitors from closely related series established the differences in the binding mode of carboxylic acid-based inhibitors (11c,c') relative to the corresponding hydroxamic acids (16a,a').
