184041-10-9Relevant articles and documents
Discovery of Potent, Selective, and Orally Active Carboxylic Acid Based Inhibitors of Matrix Metalloproteinase-13
Monovich, Lauren G.,Tommasi, Ruben A.,Fujimoto, Roger A.,Blancuzzi, Vincent,Clark, Kirk,Cornell, Wendy D.,Doti, Robert,Doughty, John,Fang, James,Farley, David,Fitt, John,Ganu, Vishwas,Goldberg, Ronald,Goldstein, Robert,Lavoie, Stacey,Kulathila, Raviraj,Macchia, William,Parker, David T.,Melton, Richard,O'Byrne, Elizabeth,Pastor, Gary,Pellas, Theodore,Quadros, Elizabeth,Reel, Noela,Roland, Dennis M.,Sakane, Yumi,Singh, Hem,Skiles, Jerry,Somers, Joseph,Toscano, Karen,Wigg, Andrew,Zhou, Siyuan,Zhu, Lijuan,Shieh, Wen-Chung,Xue, Song,McQuire, Leslie W.
supporting information; experimental part, p. 3523 - 3538 (2010/03/30)
The matrix metalloproteinase enzyme MMP-13 plays a key role in the degradation of type II collagen in cartilage and bone in osteoarthritis (OA). An effective MMP-13 inhibitor would therefore be a novel disease modifying therapy for the treatment of arthritis. Our efforts have resulted in the discovery of a series of carboxylic acid inhibitors of MMP-13 that do not significantly inhibit the related MMP-1 (collagenase-1) or tumor necrosis factor-α (TNF-α) converting enzyme (TACE). It has previously been suggested (but not proven) that inhibition of the latter two enzymes could lead to side effects. A promising carboxylic acid lead 9 was identified and a convergent synthesis developed. This paper describes the optimization of 9 and the identification of a compound 24f for further development. Compound 24f is a subnanomolar inhibitor of MMP-13 (IC50 value 0.5 nM and Ki of 0.19 nM) having no activity against MMP-1 or TACE (IC50 of >10000 nM). Furthermore, in a rat model of MMP-13-induced cartilage degradation, 24f significantly reduced proteoglycan release following oral dosing at 30 mg/kg (75% inhibition, p 0.05) and at 10 mg/kg (40% inhibition, p 0.05).
N-aryl thienyl-, furyl-, and pyrrolyl-sulfonamides and derivatives thereof that modulate the activity of endothelin
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Page column 106, (2010/01/30)
Thienyl-, furyl- and pyrrolyl-sulfonamides and methods for modulating or altering the activity of the endothelin family of peptides are provided. In particular, N-(isoxazolyl)thienylsulfonamides, N-(isoxazolyl)furylsulfonamides and N-(isoxazolyl)pyrrolylsulfonamides and methods using these sulfonamides for inhibiting the binding of an endothelin peptide to an endothelin receptor by contacting the receptor with the sulfonamide are provided. Methods for treating endothelin-mediated disorders by administering effective amounts of one or more of these sulfonamides or prodrugs thereof that inhibit or increase the activity of endothelin are also provided.
The discovery and structure - Activity relationships of nonpeptide, low molecular weight antagonists selective for the endothelin ET(B) receptor
Chan, Ming Fai,Kois, Adam,Verner, Erik J.,Raju, Bore G.,Castillo, Rosario S.,Wu, Chengde,Okunm, Ilya,Stavros, Fiona D.,Balaji
, p. 2301 - 2316 (2007/10/03)
The systematic modification of the ET(A) selective N-(5-isoxazolyl)benzene-sulfonamide endothelin antagonists to give ET(B) selective antagonists is reported. The reversal in selectivity was brought about by substitution of the 4-position with aryl and substituted aryl groups. Of all the aromatic substituents studied, the para-tolyl group gave rise to the most active and selective ET(B) antagonist. Larger substituents caused a decrease in both ET(B) activity and selectivity. A similar trend was observed by substitution at the 5-position of the N-(5-isoxazolyl)-2-thiophenesulfonamide ET(A) receptor antagonists. The para-tolyl group was again found to be optimal for the ET(B) activity and selectivity. The structural features that were found to be favorable for binding to the ET(B) receptor, that is, the presence of a linear, conjugated π-system of definite shape and size, have been successfully incorporated into the design of ET(B) selective polycyclic aromatic sulfonamides antagonists. Copyright (C) 1998 Elsevier Science Ltd.
