ABSTRACT
Inhibition of hydroxy acid oxidase 1 (HAO1) is a strategy to mitigate the accumulation of toxic oxalate that results from reduced activity of alanine-glyoxylate aminotransferase (AGXT) in primary hyperoxaluria 1 (PH1) patients. DNA-Encoded Chemical Library (DECL) screening provided two novel chemical series of potent HAO1 inhibitors, represented by compounds 3-6. Compound 5 was further optimized via various structure-activity relationship (SAR) exploration methods to 29, a compound with improved potency and absorption, distribution, metabolism, and excretion (ADME)/pharmacokinetic (PK) properties. Since carboxylic acid-containing compounds are often poorly permeable and have potential active glucuronide metabolites, we undertook a brief, initial exploration of acid replacements with the aim of identifying non-acid-containing HAO1 inhibitors. Structure-based drug design initiated with Compound 5 led to the identification of a nonacid inhibitor of HAO1, 31, which has weaker potency and increased permeability.
Subject(s)
Alcohol Oxidoreductases/antagonists & inhibitors , DNA/chemistry , Small Molecule Libraries/chemistry , Alcohol Oxidoreductases/metabolism , Animals , Binding Sites , Crystallography, X-Ray , DNA/metabolism , Drug Design , Half-Life , Humans , Hyperoxaluria, Primary/metabolism , Hyperoxaluria, Primary/pathology , Indoles/chemistry , Indoles/metabolism , Male , Mice , Molecular Docking Simulation , Small Molecule Libraries/metabolism , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/metabolism , Transaminases/genetics , Transaminases/metabolismABSTRACT
Design, synthesis and structure-activity relationship of a series of biphenylsulfonamido-3-methylbutanoic acid based aggrecanase-1 inhibitors are described. In addition to robust aggrecanase-1 inhibition, these compounds also exhibit potent MMP-13 activity. In cell-based cartilage explants assay compound 48 produced 87% inhibition of proteoglycan degradation at 10 µg/mL. Good pharmacokinetic properties were demonstrated by 46 with a half-life of 6h and bioavailability of 23%.
Subject(s)
ADAM Proteins/antagonists & inhibitors , ADAM Proteins/metabolism , Biphenyl Compounds/pharmacology , Procollagen N-Endopeptidase/antagonists & inhibitors , Procollagen N-Endopeptidase/metabolism , Protease Inhibitors/pharmacology , Sulfonamides/pharmacology , ADAMTS4 Protein , Animals , Biphenyl Compounds/chemistry , Biphenyl Compounds/pharmacokinetics , Drug Design , Humans , Male , Matrix Metalloproteinase 13/metabolism , Models, Molecular , Osteoarthritis/drug therapy , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacokinetics , Proteoglycans/metabolism , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacokineticsABSTRACT
The prevention of aggrecan (a key component of cartilage) cleavage via the inhibition of aggrecanase-1 may provide a unique opportunity to stop the progression of cartilage degradation in osteoarthritis. The evaluation of a series of biphenylsulfonamides resulted in the identification of the ((4-keto)-phenoxy)methyl biphenyl-4-sulfonamides analogs (19-21 and 24) with improved Agg-1 inhibition and MMP-2, MMP-13 activity.
Subject(s)
ADAM Proteins/antagonists & inhibitors , ADAM Proteins/metabolism , Chemistry, Pharmaceutical/methods , Osteoarthritis/drug therapy , Procollagen N-Endopeptidase/antagonists & inhibitors , Procollagen N-Endopeptidase/metabolism , Sulfonamides/chemical synthesis , ADAMTS4 Protein , Cartilage/drug effects , Cartilage/metabolism , Drug Design , Humans , Inhibitory Concentration 50 , Matrix Metalloproteinase 13/metabolism , Matrix Metalloproteinase 2/metabolism , Models, Chemical , Molecular Conformation , Proteoglycans/chemistry , Sulfonamides/pharmacologyABSTRACT
N-((8-Hydroxy-5-substituted-quinolin-7-yl)(phenyl)methyl)-2-phenyloxy/amino-acetamide inhibitors of ADAMTS-5 (Aggrecanase-2) have been prepared. Selected compounds 10, 14, 25, and 53 show sub-microM ADAMTS-5 potency and good selectivity over the related metalloproteases ADAMTS-4 (Aggrecanase-1), MMP-13, and MMP-12. Compound 53 shows a good balance of potent ADAMTS-5 inhibition, moderate CYP3A4 inhibition and good rat liver microsome stability. This series of compounds represents progress towards selective ADAMTS-5 inhibitors as disease modifying osteoarthritis agents.
Subject(s)
ADAM Proteins/antagonists & inhibitors , ADAM Proteins/chemistry , Acetamides/chemical synthesis , Acetamides/pharmacology , ADAM Proteins/metabolism , ADAMTS4 Protein , ADAMTS5 Protein , Animals , Chemistry, Pharmaceutical/methods , Cytochrome P-450 CYP3A , Cytochrome P-450 CYP3A Inhibitors , Cytochrome P-450 Enzyme Inhibitors , Drug Design , Humans , Inhibitory Concentration 50 , Microsomes, Liver/drug effects , Models, Chemical , Osteoarthritis/drug therapy , Procollagen N-Endopeptidase/metabolism , RatsABSTRACT
5'-Phenyl-3'H-spiro[indoline-3,2'-[1,3,4]thiadiazol]-2-one inhibitors of ADAMTS-5 (Aggrecanase-2) have been prepared via commercially available starting materials. Selected compounds 23, 33-35 show sub-micromolar ADAMTS-5 potency and strong SAR trends with selectivity over the related metalloproteases ADAMTS-4 (Aggrecanase-1), MMP12, and MMP13. This series of compounds represents progress toward a selective ADAMTS-5 inhibitor as a disease modifying osteoarthritis drug.
Subject(s)
Endopeptidases/metabolism , Indoles/chemistry , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Thiadiazoles/chemistry , Molecular Structure , Protease Inhibitors/chemical synthesis , Spiro Compounds/chemical synthesis , Structure-Activity Relationship , Thiadiazoles/chemical synthesis , Thiadiazoles/pharmacologyABSTRACT
5-Benzylidene-2-thioxo-thiazolidin-4-one inhibitors of ADAMTS-5 (Aggrecanase-2) have been prepared via commercially available starting materials. The identified compounds show micromolar ADAMTS-5 potency and demonstrate SAR trends for both the aryl group and thioxothiazolidinone zinc chelator. This series of compounds represents steps toward a metalloprotease inhibitor as a disease-modifying osteoarthritis drug.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Thiazolidinediones/chemical synthesis , Thiazolidinediones/pharmacology , ADAMTS5 Protein , Chelating Agents , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Humans , Metalloproteases/antagonists & inhibitors , Osteoarthritis/drug therapy , Structure-Activity Relationship , ZincABSTRACT
A series of 5-((1H-pyrazol-4-yl)methylene)-2-thioxothiazolidin-4-one inhibitors of ADAMTS-5 (aggrecanase-2) is described. These compounds show microM functional inhibition of ADAMTS-5, and represent a new class of agents with the potential of inhibiting degradation of aggrecan, a major component of cartilage which is lost in osteoporosis. Compound 12 is noteworthy in that it has an ADAMTS-5 IC50: 1.1 microM and shows >40-fold functional selectivity over ADAMTS-4 (aggrecanase-1).
Subject(s)
ADAM Proteins/antagonists & inhibitors , Thiazolidinediones/chemical synthesis , ADAMTS4 Protein , ADAMTS5 Protein , Aggrecans/drug effects , Aggrecans/metabolism , Cartilage , Humans , Inhibitory Concentration 50 , Osteoporosis/drug therapy , Procollagen N-Endopeptidase , Structure-Activity Relationship , Thiazolidinediones/pharmacologyABSTRACT
Members of the ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) family share common structural features including a disintegrin domain, a zinc metalloprotease domain, and at least one thrombospondin motif. Aberrant expression of several of these proteins has led to an understanding of their role in human disease; however, a link to function for many has not yet been made. One such uncharacterized family member, ADAMTS-8, shares significant protein sequence homology with a subgroup of ADAMTSs that includes ADAMTS-1, ADAMTS-4, ADAMTS-5, and ADAMTS-15. Each of these proteases has been shown to cleave 'aggrecanase-susceptible' site(s) within the extracellular matrix (ECM) proteoglycan aggrecan, and ADAMTS-4 and ADAMTS-5 have been postulated to play a role in the depletion of articular cartilage in osteoarthritic disease. Based on sequence relationships, in the present study we examined the ability of ADAMTS-8 to exhibit 'aggrecanase' activity. A neoepitope monoclonal antibody (MAb; AGG-C1; anti-NITEGE373) was developed and used to demonstrate the ability of ADAMTS-8 to cleave aggrecan at the aggrecanase-susceptible Glu373-Ala374 peptide bond. In addition, expression analyses demonstrated the presence of ADAMTS-8 mRNA transcripts in normal and osteoarthritic human cartilage.
