20443-74-7Relevant articles and documents
3-Arylsulfonyl-2 (substituted methyl) propanoic acid derivatives as matrix metalloproteinase inhibitors
-
Page column 19, (2010/02/07)
Compounds which are 3-arylsulfonyl-2-methyl propanoic acid derivatives of formula (I): wherein X is HO—NH— or HO—, R1 is selected from phenyl, 4-chlorophenyl, 4-florophenyl, 4-cyanophenyl, benzamido (i.e., —NH—CO-Ph) and benzamido substituted on the terminal phenyl ring by C1-C4alkyl, fluoro, chloro, cyano or C1-4alkoxy; R2is selected from (a) —S—Ar or —S—CH2—Ar wherein Ar is an aromatic moiety; (b) —O—Ar wherein Ar is as defined above; (c) —S-Het or —S—CH2-Het wherein Het is a heterocyclic ring; and (d) 2,5-dioxo-1-imidazolidinyl or 2,4-dioxo-1-imidazolinyl; and the pharmaceutically acceptable salts thereof; have potent and selective inhibitory activity against matrix metalloproteinases (MMPs) and can thus be used in the treatment and prevention of diseases mediated by MMPs.
Sulfonylamino derivatives which inhibit matrix-degrading metalloproteinases
-
, (2008/06/13)
Compounds of formula (I) wherein W is —OH or —NHOH; X is an optionally substituted heterocycle, NR1SO2R2, heterocyclylalkythio, CONR2R3or NR1COR2; Y, Z, R1-R3and n are as defined in the application. Compounds (I) are inhibitors of matrix-degrading metalloproteinases and are use for the treatment of related conditions.
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').
