A molecular modeling analysis of novel non-hydroxamate inhibitors of TACE

• Published in: Bioorganic & medicinal chemistry letters Vol. 17; no. 5; pp. 1408 - 1412
• Main Authors: Sheppeck, James E., Tebben, Andrew, Gilmore, John L., Yang, Anle, Wasserman, Zelda R., Decicco, Carl P., Duan, James J.-W.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.03.2007; Elsevier
• Subjects: ADAM Proteins - antagonists & inhibitors; ADAM Proteins - chemistry; ADAM17 Protein; Barbiturate; Binding Sites; Biological and medical sciences; Humans; Hydantoin; Hydantoins - chemistry; Hydantoins - pharmacology; Hydroxamate; Hydroxamic Acids - chemistry; Hydroxamic Acids - pharmacology; Lactams - chemistry; Lactams - pharmacology; Medical sciences; Metalloprotease; Metalloproteinase; Miscellaneous; MMP; Modeling; Models, Molecular; Molecular Conformation; Non-hydroxamate; Pharmacology. Drug treatments; Pyrimidinones - chemistry; Pyrimidinones - pharmacology; Structure-Activity Relationship; TACE; TACE inhibitor; TNF; Zinc - chemistry; TACE inhibitor; MMP; Non-hydroxamate; Hydroxamate; Barbiturate; Hydantoin; TACE; Metalloprotease; Metalloproteinase; Modeling; TNF; Active site; Metalloendopeptidases; Selectivity; Molecular model; Barbiturates; Tumor necrosis factor α; Molecular rigidity; Enzyme; Cytokine; Prediction; Enzyme inhibitor; Quinoline derivatives; Steric hindrance; Hydantoins; In vitro; Biological activity; Spiran; Peptidases; Synthetic product; Hydrolases; Pyrimidine derivatives; Crystalline structure
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2006.11.082

We have developed a number of hydroxamate and non-hydroxamate inhibitors of TACE that possess the selective quinolinemethoxy P1′ group. Using the X-ray co-crystal structure of our hydroxamate IK682 and TACE, and a co-crystal structure of a pyrimidinetrione in MMP-8, we have developed a highly plausible pharmacophore model of how our pyrimidinetrione and hydantoin inhibitors bind to TACE. Recently, an X-ray co-crystal structure of our hydroxamate inhibitor IK682 and TACE [Niu, X.; Umland, S.; Ingram, R.; Beyer, B. M.; Liu, Y.-H.; Sun, J.; Lundell, D.; Orth, P. Arch. Biochem. Biophys. 2006, 451, 43–50] was published that explicitly shows the orientation of the hydroxamate and the TACE-selective 4-[(2-methyl-4-quinolinyl)methoxy]phenyl P1′ group in the S1′ and S3′ sites. The preceding paper described a novel series of potent and TACE-selective hydantoins and we previously described pyrimidinetrione (barbiturate) inhibitors of TACE, both of which contain the same P1′ group as IK682. Using this TACE-selective P1′ group as an anchor, stereochemical and conformational constraints in the inhibitors, and restrictions to the active site Zn coordination geometry, we developed a highly plausible and predictive pharmacophore model that rationalizes the observed TACE activity of all three inhibitors.