Synthesis and activity of tryptophan sulfonamide derivatives as novel non-hydroxamate TNF-α converting enzyme (TACE) inhibitors

• Published in: Bioorganic & medicinal chemistry Vol. 17; no. 11; pp. 3857 - 3865
• Main Authors: Park, Kaapjoo, Gopalsamy, Ariamala, Aplasca, Alexis, Ellingboe, John W., Xu, Weixin, Zhang, Yuhua, Levin, Jeremy I.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.06.2009; Elsevier
• Subjects: ADAM Proteins - antagonists & inhibitors; ADAM17 Protein; Animals; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Carboxylic Acids - chemistry; Cell Line; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Inhibitory Concentration 50; Martix metalloprotease (MMP); Medical sciences; Models, Molecular; Molecular Structure; Non-hydroxamate; Pharmacology. Drug treatments; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; TNF-α converting enzyme (TACE) inhibitor; Tryptophan - analogs & derivatives; Tryptophan - chemical synthesis; Tryptophan - chemistry; Tryptophan - pharmacology; Tryptophan sulfonamide derivatives; Non-hydroxamate; TNF-α converting enzyme (TACE) inhibitor; Martix metalloprotease (MMP); Tryptophan sulfonamide derivatives; Metalloendopeptidases; Selectivity; Modeling; Structure activity relation; Molecular model; Inhibition; Chemical synthesis; Tumor necrosis factor α; Sulfonamide; Monocyte; Enzyme; Rodentia; Antiinflammatory agent; Cytokine; Benzene derivatives; Enzyme inhibitor; Inhibitor enzyme complex; In vitro; Peptidases; α-Aminoacid; Vertebrata; Mammalia; Cell line; Mouse; Hydrolases; Indole derivatives
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2009.04.033

A novel series of non-hydroxamate tryptophan sulfonamide derivatives containing a butynyloxy P1′ moiety was identified as inhibitors of TNF-α Converting Enzyme (TACE). The structure activity relationship of the series was examined via substitution on the tryptophan indole ring. Of the compounds investigated, 2-(4-(but-2-ynyloxy)phenylsulfonamido)-3-(1-(4-methoxybenzyl)-1 H-indol-3-yl)propanoic acid ( 12p) has the best in vitro potency against isolated TACE enzyme with an IC 50 of 80 nM. Compound 12p also shows good selectivity over MMP-1, -13, -14. A novel series of non-hydroxamate tryptophan sulfonamide derivatives containing a butynyloxy P1′ moiety was identified as inhibitors of TNF-α converting enzyme (TACE). The structure–activity relationship of the series was examined via substitution on the tryptophan indole ring. Of the compounds investigated, 2-(4-(but-2-ynyloxy)phenylsulfonamido)-3-(1-(4-methoxybenzyl)-1 H-indol-3-yl)propanoic acid ( 12p) has the best in vitro potency against isolated TACE enzyme with an IC 50 of 80 nM. Compound 12p also shows good selectivity over MMP-1, -13, -14.