论文信息 - Synthesis and biological activity of selective pipecolic acid-based TNF-alpha converting enzyme (TACE) inhibitors.

Synthesis and biological activity of selective pipecolic acid-based TNF-alpha converting enzyme (TACE) inhibitors.

A series of novel, selective TNF-alpha converting enzyme inhibitors based on 4-hydroxy and 5-hydroxy pipecolate hydroxamic acid scaffolds is described. The potency and selectivity of TACE inhibition is dramatically influenced by the nature of the sulfonamide group which interacts with the S1' site of the enzyme. Substituted 4-benzyloxybenzenesulfonamides exhibit excellent TACE potency with >100x selectivity over inhibition of matrix metalloprotease-1 (MMP-1). Alkyl substituents on the ortho position of the benzyl ether moiety give the most potent inhibition of TNF-alpha release in LPS-treated human whole blood.

[1] J. Gillard,et al. Preparation of (2S,4R)-4-Hydroxypipecolic Acid and Derivatives , 1996 .

[2] I. Coutts,et al. The reaction of lithium trimethylsilyldiazomethane with pyroglutamates — a facile synthesis of 6-diazo-5-oxo-norleucine and derivatives , 1998 .

[3] Kee-In Lee,et al. Synthesis of 5-oxo-l-pipecolic acid derivatives by rhodium(II) acetate catalyzed cyclization of diazoketones , 1992 .

[4] M. Feldmann,et al. Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? , 2001, Annual review of immunology.

[5] Nicole Nelson,et al. A metalloproteinase disintegrin that releases tumour-necrosis factor-α from cells , 1997, Nature.

[6] M. Lambert,et al. Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-α , 1997, Nature.

[7] M. Green,et al. A high throughput fluorogenic substrate for interstitial collagenase (MMP-1) and gelatinase (MMP-9). , 1993, Analytical biochemistry.

[8] R. Huber,et al. Crystal structure of the catalytic domain of human tumor necrosis factor-alpha-converting enzyme. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[9] H. V. Van Wart,et al. Crystal structures of MMP-1 and -13 reveal the structural basis for selectivity of collagenase inhibitors , 1999, Nature Structural Biology.