91493-72-0Relevant academic research and scientific papers
Biaryl sulfonamides and methods for using same
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Page/Page column 27, (2010/02/12)
The present invention relates to biaryl sulfonamides and their use as, for example, metalloproteinase inhibitors.
Identification of potent and selective MMP-13 inhibitors
Wu, Junjun,Rush III, Thomas S.,Hotchandani, Rajeev,Du, Xuemei,Geck, Mary,Collins, Elisabeth,Xu, Zhang-Bao,Skotnicki, Jerry,Levin, Jeremy I.,Lovering, Frank E.
, p. 4105 - 4109 (2007/10/03)
A potent, selective series of MMP-13 inhibitors has been derived from a weak (3.2 μM) inhibitor that did not bear a zinc chelator. Structure-based drug design strategies were employed to append a Zn-chelating group to one end of the molecule and functionality to enhance selectivity to the other. A compound from this series demonstrated rat oral bioavailability and efficacy in a bovine articular cartilage explant model.
Synthesis of radiolabeled biphenylsulfonamide matrix metalloproteinase inhibitors as new potential PET cancer imaging agents
Fei, Xiangshu,Zheng, Qi-Huang,Liu, Xuan,Wang, Ji-Quan,Sun, Hui Bin,Mock, Bruce H.,Stone, K. Lee,Miller, Kathy D.,Sledge, George W.,Hutchins, Gary D.
, p. 2217 - 2222 (2007/10/03)
Novel matrix metalloproteinase (MMP) inhibitor radiotracers, (S)-3-methyl-2-(2′,3′,4′-methoxybiphenyl-4-sulfonylamino)- butyric acid [11C]methyl ester (1a-c), (S)-3-methyl-2-(2′,3′,4′-fluorobiphenyl-4-sulfonylamino)- butyric acid [11C]methyl ester (1d-f), and (S)-3-methyl-2-(4′-nitrobiphenyl-4-sulfonylamino)-butyric acid [11C]methyl ester (1g), a series of substituted biphenylsulfonamide derivatives, have been synthesized for evaluation as new potential positron emission tomography (PET) cancer imaging agents.
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').
