Document Report Card

ID: ALA1134554

Journal: J Med Chem

Title: Design, synthesis, and structure-activity relationships of macrocyclic hydroxamic acids that inhibit tumor necrosis factor alpha release in vitro and in vivo.

Authors: Xue CB, Voss ME, Nelson DJ, Duan JJ, Cherney RJ, Jacobson IC, He X, Roderick J, Chen L, Corbett RL, Wang L, Meyer DT, Kennedy K, DeGradodagger WF, Hardman KD, Teleha CA, Jaffee BD, Liu RQ, Copeland RA, Covington MB, Christ DD, Trzaskos JM, Newton RC, Magolda RL, Wexler RR, Decicco CP.

Abstract: To search for TNF-alpha (tumor necrosis factor alpha) converting enzyme (TACE) inhibitors, we designed a new class of macrocyclic hydroxamic acids by linking the P1 and P2' residues of acyclic anti-succinate-based hydroxamic acids. A variety of residues including amide, carbamate, alkyl, sulfonamido, Boc-amino, and amino were found to be suitable P1-P2' linkers. With an N-methylamide at P3', the 13-16-membered macrocycles prepared exhibited low micromolar activities in the inhibition of TNF-alpha release from LPS-stimulated human whole blood. Further elaboration in the P3'-P4' area using the cyclophane and cyclic carbamate templates led to the identification of a number of potent analogues with IC(50) values of

CiteXplore: 11472217

DOI: 10.1021/jm010127e