Hydantoins, triazolones, and imidazolones as selective non-hydroxamate inhibitors of tumor necrosis factor-α converting enzyme (TACE)

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 10, 2007, Pages 2769-2774

  Sheppeck II, James E ^a   Gilmore, John L ^a   Tebben, Andrew ^a   Xue, Chu Biao ^a   Liu, Rui Qin ^a   Decicco, Carl P ^a   Duan, James J W ^a  

^a BRISTOL MYERS SQUIBB   (United States)

Author keywords

Matrix metalloprotease; MMP; Non hydroxamate; TACE; TACE inhibitor; TNF

Indexed keywords

BARBITURIC ACID DERIVATIVE; BENZOIC ACID DERIVATIVE; HYDANTOIN; HYDROXAMIC ACID; IMIDAZOLONE; METALLOPROTEINASE; PYRIMIDINETRIONE; TRIAZOLONE; TUMOR NECROSIS FACTOR ALPHA CONVERTING ENZYME; TUMOR NECROSIS FACTOR ALPHA CONVERTING ENZYME INHIBITOR; UNCLASSIFIED DRUG;

ARTICLE; COMPARATIVE STUDY; DRUG IDENTIFICATION; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME STRUCTURE; PHARMACOPHORE; X RAY CRYSTALLOGRAPHY;

ADAM PROTEINS; ENZYME INHIBITORS; HYDANTOINS; HYDROXAMIC ACIDS; IMIDAZOLES; MODELS, MOLECULAR; MOLECULAR STRUCTURE; TRIAZOLES;

EID: 34247326550     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2007.02.076     Document Type: Article

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24. 3N, DMF) followed by treating with 2 M NaOH overnight followed by Boc deprotection with TFA/DCM.
25. 2; 100% yield) followed by coupling to the P1′ acid using the same method as used for compounds 6 and 9 provided 15.
26. a would not benefit as much from resonance stabilization due to cross-conjugation.
27. Compounds were modeled in chain A of the TACE crystal structure 2FV5. Waters were removed from the structure except for those within the active site that formed >1 direct interactions with the protein. The complex was minimized with the OPLSAA-2005 force field using the GB/SA water model as implemented in Macromodel. IK682 and residues within 5 Ǻ were allowed to move freely, residues 5-10 Ǻ were constrained with a force constant of 200, and residues >10 Ǻ were frozen. The structure was first subjected to 500 steps of SD minimization followed by TNCG minimization to a gradient change of <0.05. The resulting minimized structure was used as the starting template for ligand modeling. Modeled ligands were constructed manually by removing the hydroxamate moiety from IK682 and replacing it with the appropriate functional group. The ZBGs were assumed to be in the enol tautomeric form. A conformational search was then carried out using the conformational search module of Macromodel allowing only the newly constructed functional group to move while freezing the remaining coordinates. The resulting conformations were aligned onto IK682 in the TACE/IK682 minimized complex and the best fitting conformation (as judged by sterics and hydrogen bonding) selected manually. The complex of the new ligand in TACE was then refined by the minimization protocol described above.
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31. The hydantoin group is found in phenytoin, the barbiturate is found in pentobarbital, and the triazolone is found in aprepitant.