ABSTRACT
N-Hydroxy-2-arylisoindoline-4-carboxamides are potent and selective inhibitors of HDAC11. The discovery, synthesis, and structure activity relationships of this novel series of inhibitors are reported. An advanced analog (FT895) displays promising cellular activity and pharmacokinetic properties that make it a useful tool to study the biology of HDAC11 and its potential use as a therapeutic target for oncology and inflammation indications.
Subject(s)
Drug Discovery , Enzyme Inhibitors/pharmacology , Histone Deacetylases/metabolism , Isoindoles/pharmacology , Animals , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Isoindoles/chemical synthesis , Isoindoles/chemistry , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Molecular Structure , Recombinant Proteins/metabolism , Structure-Activity RelationshipABSTRACT
Through fragment-based drug design focused on engaging the active site of IRAK4 and leveraging three-dimensional topology in a ligand-efficient manner, a micromolar hit identified from a screen of a Pfizer fragment library was optimized to afford IRAK4 inhibitors with nanomolar potency in cellular assays. The medicinal chemistry effort featured the judicious placement of lipophilicity, informed by co-crystal structures with IRAK4 and optimization of ADME properties to deliver clinical candidate PF-06650833 (compound 40). This compound displays a 5-unit increase in lipophilic efficiency from the fragment hit, excellent kinase selectivity, and pharmacokinetic properties suitable for oral administration.
Subject(s)
Drug Discovery , Interleukin-1 Receptor-Associated Kinases/antagonists & inhibitors , Isoquinolines/pharmacology , Protein Kinase Inhibitors/pharmacology , Administration, Oral , Dose-Response Relationship, Drug , Humans , Interleukin-1 Receptor-Associated Kinases/metabolism , Isoquinolines/administration & dosage , Isoquinolines/chemistry , Lactams , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
Previously we reported the discovery of CRA-898 (1), a diazine indole acetic acid containing CRTH2 antagonist. This compound had good in vitro and in vivo potency, low rates of metabolism, moderate permeability, and good oral bioavailability in rodents. However, it showed low oral exposure in nonrodent safety species (dogs and monkeys). In the current paper, we wish to report our efforts to understand and improve the poor PK in nonrodents and development of a new isoquinolinone subseries that led to identification of a new development candidate, CRA-680 (44). This compound was efficacious in both a house dust mouse model of allergic lung inflammation (40 mg/kg qd) as well as a guinea pig allergen challenge model of lung inflammation (20 mg/kg bid).
Subject(s)
Acetates/chemistry , Hypersensitivity/drug therapy , Inflammation/drug therapy , Quinolones/pharmacology , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Humans , Quinolones/chemistry , Th2 CellsABSTRACT
New classes of CRTH2 antagonists, the pyridazine linker containing indole acetic acids, are described. The initial hit 1 had good potency but poor permeability, metabolic stability, and PK. Initial optimization led to compounds of type 2 with low oxidative metabolism but poor oral bioavailability. Poor permeability was identified as a liability for these compounds. Addition of a linker between the indole and diazine moieties afforded a series with good potency, low rates of metabolism, moderate permeability, and good oral bioavailability in rodents. 32 was identified as the development track candidate. It was potent in cell based, binding, and whole blood assays and exhibited good PK profile. It was efficacious in mouse models of contact hypersensitivity (1 mg/kg b.i.d.) and house dust (20 mg/kg q.d.) when dosed orally. In sheep asthma, administration at 1 mg/kg iv completely blocked the LAR and AHR and attenuated the EAR phase.
Subject(s)
Hypersensitivity/drug therapy , Indoleacetic Acids/chemical synthesis , Pyridazines/chemical synthesis , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Bronchoconstriction/drug effects , Caco-2 Cells , Cell Shape/drug effects , Chemotaxis, Leukocyte/drug effects , Dermatitis, Contact/drug therapy , Dermatitis, Contact/immunology , Eosinophils/cytology , Eosinophils/drug effects , Female , High-Throughput Screening Assays , Humans , Hypersensitivity/immunology , Immunoassay , Indoleacetic Acids/pharmacokinetics , Indoleacetic Acids/pharmacology , Inflammation/drug therapy , Inflammation/immunology , Mice , Mice, Inbred BALB C , Microsomes, Liver/metabolism , Permeability , Pyridazines/pharmacokinetics , Pyridazines/pharmacology , Pyroglyphidae/immunology , Rats , Sheep , Structure-Activity RelationshipABSTRACT
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
Potent 3,4-disubstituted benzofuran P1' MMP-13 inhibitors have been prepared. Selectivity over MMP-2 was achieved through a substituent at the C4 position of the benzofuran P1' moiety of the molecule. By replacing a backbone benzene with a pyridine and valine with threonine, compounds (e.g., 44) with greatly reduced plasma protein binding were also obtained.
Subject(s)
Benzofurans/chemistry , Matrix Metalloproteinase Inhibitors , Protease Inhibitors/chemistry , Animals , Benzofurans/chemical synthesis , Benzofurans/pharmacology , Matrix Metalloproteinase 13/metabolism , Matrix Metalloproteinase 2/metabolism , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Protein Binding , Rabbits , Serum Albumin/chemistry , Structure-Activity RelationshipABSTRACT
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
The optimization of a class of indole cPLA 2 alpha inhibitors is described herein. The importance of the substituent at C3 and the substitution pattern of the phenylmethane sulfonamide region are highlighted. Optimization of these regions led to the discovery of 111 (efipladib) and 121 (WAY-196025), which are shown to be potent, selective inhibitors of cPLA 2 alpha in a variety of isolated enzyme assays, cell based assays, and rat and human whole blood assays. The binding of these compounds has been further examined using isothermal titration calorimetry. Finally, these compounds have shown efficacy when dosed orally in multiple acute and chronic prostaglandin and leukotriene dependent in vivo models.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Benzoates/chemical synthesis , Group IV Phospholipases A2/antagonists & inhibitors , Sulfonamides/chemical synthesis , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Arthritis, Experimental/drug therapy , Benzoates/chemistry , Benzoates/pharmacology , Biological Availability , Bronchoconstriction/drug effects , Calorimetry , Carrageenan , Cell Line , Cyclooxygenase 2 Inhibitors/chemical synthesis , Cyclooxygenase 2 Inhibitors/chemistry , Cyclooxygenase 2 Inhibitors/pharmacology , Edema/chemically induced , Edema/drug therapy , Humans , In Vitro Techniques , Isoenzymes/antagonists & inhibitors , Male , Mice , Protein Binding , Rats , Rats, Sprague-Dawley , Sheep , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacologyABSTRACT
We have previously reported the discovery and initial SAR of the [1,7]naphthyridine-3-carbonitriles and quinoline-3-carbonitriles as Tumor Progression Loci-2 (Tpl2) kinase inhibitors. In this paper, we report new SAR efforts which have led to the identification of 4-alkylamino-[1,7]naphthyridine-3-carbonitriles. These compounds show good in vitro and in vivo activity against Tpl2 and improved pharmacokinetic properties. In addition they are highly selective for Tpl2 kinase over other kinases, for example, EGFR, MEK, MK2, and p38. Lead compound 4-cycloheptylamino-6-[(pyridin-3-ylmethyl)-amino]-[1,7]naphthyridine-3-carbonitrile (30) was efficacious in a rat model of LPS-induced TNF-alpha production.
Subject(s)
Enzyme Inhibitors/pharmacology , MAP Kinase Kinase Kinases/metabolism , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins/metabolism , Animals , Binding, Competitive , Cycloheptanes/chemistry , Cycloheptanes/pharmacology , Enzyme Inhibitors/chemistry , ErbB Receptors/antagonists & inhibitors , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Lipopolysaccharides/pharmacology , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Naphthyridines/chemistry , Naphthyridines/pharmacology , Nitriles/chemistry , Nitriles/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Rats , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/biosynthesis , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitorsABSTRACT
Tumor progression loci-2 (Tpl2) (Cot/MAP3K8) is a serine/threonine kinase in the MAP3K family directly upstream of MEK. Recent studies using Tpl2 knockout mice have indicated an important role for Tpl2 in the lipopolysaccharide (LPS) induced production of tumor necrosis factor alpha (TNF-alpha) and other proinflammatory cytokines involved in diseases such as rheumatoid arthritis. Initial 4-anilino-6-aminoquinoline-3-carbonitrile leads showed poor selectivity for Tpl2 over epidermal growth factor receptor (EGFR) kinase. Using molecular modeling and crystallographic data of the EGFR kinase domain with and without an EGFR kinase-specific 4-anilinoquinazoline inhibitor (erlotinib, Tarceva), we hypothesized that we could diminish the inhibition of EGFR kinase by substitution at the C-8 position of our 4-anilino-6-aminoquinoline-3-carbonitrile leads. The 8-substituted-4-anilino-6-aminoquinoline-3-carbonitriles were prepared from the appropriate 2-substituted 4-nitroanilines. Modifications to the C-6 and C-8 positions led to the identification of compounds with increased inhibition of TNF-alpha release from LPS-stimulated rat and human blood, and these analogues were also highly selective for Tpl2 kinase over EGFR kinase. Further structure-activity based modifications led to the identification of 8-bromo-4-(3-chloro-4-fluorophenylamino)-6-[(1-methyl-1H-imidazol-4-yl)methylamino]quinoline-3-carbonitrile, which demonstrated in vitro as well as in vivo efficacy in inhibition of LPS-induced TNF-alpha production.
Subject(s)
Aminoquinolines/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Imidazoles/chemical synthesis , MAP Kinase Kinase Kinases/antagonists & inhibitors , Models, Molecular , Proto-Oncogene Proteins/antagonists & inhibitors , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Aminoquinolines/pharmacokinetics , Aminoquinolines/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Crystallography, X-Ray , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/chemistry , Erlotinib Hydrochloride , Female , Humans , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , In Vitro Techniques , MAP Kinase Kinase Kinases/biosynthesis , MAP Kinase Kinase Kinases/chemistry , Microsomes, Liver/metabolism , Protein Structure, Tertiary , Proto-Oncogene Proteins/biosynthesis , Proto-Oncogene Proteins/chemistry , Quinazolines/chemistry , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/biosynthesis , Tumor Necrosis Factor-alpha/chemistryABSTRACT
The synthesis and structure-activity studies of a series of quinoline-3-carbonitriles as inhibitors of Tpl2 kinase are described. Potent inhibitors of Tpl2 kinase with selectivity against a panel of selected kinases in enzymatic assays and specificity in cell-based phosphorylation assays in LPS-treated human monocytes were identified. Selected inhibitors with moderate activity in human whole blood assay effectively inhibited LPS/D-Gal induced TNFalpha release when administered intraperitoneally in mice.
Subject(s)
Arthritis, Rheumatoid/metabolism , MAP Kinase Kinase Kinases/antagonists & inhibitors , Nitriles/chemistry , Nitriles/pharmacology , Quinolines/chemistry , Tumor Necrosis Factor-alpha/biosynthesis , Arthritis, Rheumatoid/drug therapy , Cross-Linking Reagents/chemistry , Humans , Imidazoles/chemistry , MAP Kinase Kinase Kinases/metabolism , Molecular Structure , Monocytes/drug effects , Monocytes/metabolism , Nitriles/chemical synthesis , Structure-Activity RelationshipABSTRACT
Aggrecanases are recently discovered enzymes that cleave aggrecan, a key component of cartilage. Aggrecanase inhibitors may provide a unique means to halt the progression of cartilage destruction in osteoarthritis. The synthesis and evaluation of biphenylsulfonamidocarboxylic acid inhibitors of aggrecanase-1 are reported. Compound 24 demonstrated 89% inhibition of proteoglycan degradation at 10 microg/mL and has an oral bioavailability in rat of 35%.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Biphenyl Compounds/chemistry , Carboxylic Acids , Enzyme Inhibitors , Procollagen N-Endopeptidase/antagonists & inhibitors , Sulfonamides/chemistry , ADAMTS4 Protein , Administration, Oral , Animals , Carboxylic Acids/chemical synthesis , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , Collagenases/metabolism , Crystallography, X-Ray , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Matrix Metalloproteinase 13 , Matrix Metalloproteinase Inhibitors , Models, Molecular , Molecular Structure , Proteoglycans/drug effects , Proteoglycans/metabolism , Rats , Structure-Activity RelationshipABSTRACT
Modification of alpha-biphenylsulfonamidocarboxylic acids led to potent and selective MMP-13 inhibitors. Compound 16 showed 100% oral bioavailability in rats and demonstrated >50% inhibition of bovine cartilage degradation at 10 ng/mL.
Subject(s)
Collagenases/metabolism , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/pharmacokinetics , Matrix Metalloproteinase Inhibitors , Osteoarthritis/drug therapy , Administration, Oral , Animals , Benzofurans/chemical synthesis , Benzofurans/chemistry , Collagenases/chemistry , Drug Evaluation, Preclinical , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Inhibitory Concentration 50 , Matrix Metalloproteinase 13 , Models, Molecular , Molecular Structure , Rats , Substrate SpecificityABSTRACT
The synthesis and structure-activity studies of a series of 6-substituted-4-anilino-[1,7]-naphthyridine-3-carbonitriles as inhibitors of Tpl2 kinase are described. The early exploratory work described here may lead to the discovery of compounds with significant therapeutic potential for treating rheumatoid arthritis and other inflammatory diseases.
Subject(s)
MAP Kinase Kinase Kinases/antagonists & inhibitors , Naphthyridines/chemistry , Nitriles/chemistry , Nitriles/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins/antagonists & inhibitors , Tumor Necrosis Factor-alpha/biosynthesis , Arthritis, Rheumatoid/drug therapy , Humans , Naphthyridines/chemical synthesis , Naphthyridines/pharmacology , Nitriles/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Structure-Activity RelationshipABSTRACT
The structure-based design and synthesis of a series of novel biphenyl sulfonamide carboxylic acids as potent MMP-13 inhibitors with selectivity over MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-14, Aggrecanase 1, and TACE are described.
