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
Subject(s)
Enzyme Inhibitors/chemical synthesis , Hydroxamic Acids/chemical synthesis , Lactams/chemical synthesis , Metalloendopeptidases/antagonists & inhibitors , Tumor Necrosis Factor-alpha/antagonists & inhibitors , ADAM Proteins , ADAM17 Protein , Administration, Oral , Animals , Biological Availability , Carbamates/chemical synthesis , Carbamates/chemistry , Carbamates/pharmacokinetics , Carbamates/pharmacology , Dogs , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Humans , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacokinetics , Hydroxamic Acids/pharmacology , In Vitro Techniques , Lactams/chemistry , Lactams/pharmacokinetics , Lactams/pharmacology , Male , Mice , Stereoisomerism , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/analysisABSTRACT
Several macrocyclic, hydroxamate derivatives were synthesized and evaluated as inhibitors of matrix metalloproteinases (MMPs) and tumour necrosis factor-alpha (TNF-alpha) production. These macrocycles are anti-succinate based inhibitors linked from P1 to P2'. A variety of functionality was installed at the P1-P2' linkage, which gave inhibitors that displayed excellent MMP inhibition and good TNF-alpha suppression.
