ABSTRACT
Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease associated with irreversible progressive airflow limitation. Matrix metalloproteinase-12 (MMP-12) has been characterized to be one of the major proteolytic enzymes to induce airway remodeling, destruction of elastin and the aberrant remodeling of damaged alveoli in COPD and asthma. The goal of this project is to develop and identify an orally potent and selective small molecule inhibitor of MMP-12 for treatment of COPD and asthma. Syntheses and structure-activity relationship (SAR) studies of a series of dibenzofuran (DBF) sulfonamides as MMP-12 inhibitors are described. Potent inhibitors of MMP-12 with excellent selectivity against other MMPs were identified. Compound 26 (MMP118), which exhibits excellent oral efficacy in the MMP-12 induced ear-swelling inflammation and lung inflammation mouse models, had been successfully advanced into Development Track status.
Subject(s)
Drug Design , Matrix Metalloproteinase 12/metabolism , Matrix Metalloproteinase Inhibitors , Pulmonary Disease, Chronic Obstructive/enzymology , Animals , Asthma/drug therapy , Asthma/enzymology , Chemistry, Pharmaceutical/methods , Disease Models, Animal , Enzyme Inhibitors/pharmacology , Humans , Inflammation , Inhibitory Concentration 50 , Mice , Models, Chemical , Models, Molecular , Molecular Conformation , Pulmonary Disease, Chronic Obstructive/drug therapy , Structure-Activity Relationship , Sulfonamides/chemistry , X-RaysABSTRACT
High-throughput screening highlighted 9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile (1) as an active inhibitor of ubiquitin-specific proteases (USPs), a family of hydrolytic enzymes involved in the removal of ubiquitin from protein substrates. The chemical behavior of compound 1 was examined. Moreover, the synthesis and in vitro evaluation of new compounds, analogues of 1, led to the identification of potent and selective inhibitors of the deubiquitinating enzyme USP8.
Subject(s)
Endosomal Sorting Complexes Required for Transport/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Indenes/chemistry , Pyrazines/chemistry , Ubiquitin Thiolesterase/antagonists & inhibitors , Crystallography, X-Ray , Drug Evaluation, Preclinical , Endopeptidases/metabolism , Endosomal Sorting Complexes Required for Transport/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , High-Throughput Screening Assays , Humans , Indenes/pharmacology , Molecular Conformation , Pyrazines/chemical synthesis , Pyrazines/pharmacology , Ubiquitin Thiolesterase/metabolism , Ubiquitin-Specific Peptidase 7ABSTRACT
MMP-12 plays a significant role in airway inflammation and remodeling. Increased expression and production of MMP-12 have been observed in the lungs of asthmatic patients. Compound 27 was identified as a potent and selective MMP-12 inhibitor possessing good physicochemical properties. In pharmacological studies, the compound was orally efficacious in an MMP-12 induced ear-swelling inflammation model in the mouse with a good dose response. This compound also exhibited oral efficacy in a naturally Ascaris-sensitized sheep asthma model showing significant inhibition of the late phase response to allergen challenge. This compound has been considered for further development as a treatment therapy for asthma.
