ABSTRACT
Aggrecanases, particularly aggrecanase-1 (ADAMTS-4) and aggrecanase-2 (ADAMTS-5), are believed to be key enzymes involved in the articular cartilage breakdown that leads to osteoarthritis. Thus, aggrecanases are considered to be viable drug targets for the treatment of this debilitating disease. A series of (1S,2R,3R)-2,3-dimethyl-2-phenyl-1-sulfamidocyclopropanecarboxylates was discovered to be potent, highly selective, and orally bioavailable aggrecanase inhibitors. These compounds have unique P1' groups comprising novel piperidine- or piperazine-based heterocycles that are connected to a cyclopropane amino acid scaffold via a sulfamido linkage. These P1' groups are quite effective in imparting selectivity over other MMPs, and this selectivity was further increased by incorporation of a methyl substituent in the 2-position of the cyclopropane ring. In contrast to classical hydroxamate-based inhibitors that tend to lack metabolic stability, our aggrecanase inhibitors bear a carboxylate zinc-binding group and have good oral bioavailability. Lead compound 13b, characterized by the novel P1' portion of 1,2,3,4-tetrahydropyrido[3',4':4,5]imidazo[1,2-a]pyridine ring, is a potent and selective aggrecanse inhibitor with excellent pharmacokinetic profiles.
Subject(s)
Cyclopropanes/chemistry , Cyclopropanes/pharmacology , Drug Discovery , Endopeptidases/drug effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Animals , Crystallography, X-Ray , Cyclopropanes/pharmacokinetics , Enzyme Inhibitors/pharmacokinetics , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Mice , Mice, Knockout , Models, Molecular , Structure-Activity RelationshipABSTRACT
A series of 1-sulfonylaminocyclopropanecarboxylates was synthesized as ADAMTS-5 (Aggrecanase-2) inhibitors. After an intensive investigation of the central cyclopropane core including its absolute stereochemistry and substituents, we found compound 22 with an Agg-2 IC50=7.4 nM, the most potent ADAMTS-5 inhibitor reported so far.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Cyclopropanes/chemical synthesis , Protease Inhibitors/chemical synthesis , Sulfonamides/chemical synthesis , ADAM Proteins/metabolism , ADAMTS5 Protein , Animals , Binding Sites , Computer Simulation , Cyclopropanes/chemistry , Cyclopropanes/pharmacokinetics , Cyclopropanes/pharmacology , Drug Design , Humans , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacokinetics , Protein Binding , Rats , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacologyABSTRACT
A series of N-substituted sulfonylamino-alkanecarboxylate ADAMTS-5 (Aggrecanase-2) inhibitors has been synthesized and the in vitro enzyme SAR is discussed. This report is the first example of carboxylate-based ADAMTS-5 inhibitors which show strong potency of IC(50)<0.1muM with excellent selectivity over MMP-1 and TACE.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Protease Inhibitors/chemical synthesis , ADAMTS5 Protein , Carboxylic Acids/chemistry , Drug Design , Humans , Inhibitory Concentration 50 , Models, Chemical , Molecular Conformation , Molecular Structure , Osteoarthritis/drug therapy , Protease Inhibitors/pharmacology , Protein Structure, Tertiary , Structure-Activity RelationshipABSTRACT
[reaction: see text] The preparation and synthetic applications of a novel resin-bound isonitrile are described. The resin is an example of a novel convertible isonitrile that can be utilized in the Ugi multicomponent reaction. Base-activation of the resin-bound Ugi product results in cleavage via formation of a N-acyloxazolidone that is then trapped as a carboxylic acid ester. This resin and the methodology described are suitable for synthesizing diversity libraries of 2,5-diketopiperazines and 1,4-benzodiazepine-2,5-diones.
