ABSTRACT
11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) catalyzes the conversion of inactive glucocorticoid cortisone to its active form, cortisol. The glucocorticoid receptor (GR) signaling pathway has been linked to the pathophysiology of diabetes and metabolic syndrome. Herein, the structure-activity relationship of a series of piperazine sulfonamide-based 11ß-HSD1 inhibitors is described. (R)-3,3,3-Trifluoro-2-(5-(((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-yl)sulfonyl)thiophen-2-yl)-2-hydroxypropanamide 18a (HSD-621) was identified as a potent and selective 11ß-HSD1 inhibitor and was ultimately selected as a clinical development candidate. HSD-621 has an attractive overall pharmaceutical profile and demonstrates good oral bioavailability in mouse, rat, and dog. When orally dosed in C57/BL6 diet-induced obesity (DIO) mice, HSD-621 was efficacious and showed a significant reduction in both fed and fasting glucose and insulin levels. Furthermore, HSD-621 was well tolerated in drug safety assessment studies.
ABSTRACT
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
We report here the synthesis and SAR of a new series of thieno[3,2-d]pyrimidines as potent Tpl2 kinase inhibitors. The proposed binding mode suggests the potential flipped binding mode depending on the substitution. Biacore studies show evidence of binding of these molecules to the protein kinase. The kinome inhibition profile of these molecules suggests good selectivity.
Subject(s)
MAP Kinase Kinase Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins/antagonists & inhibitors , Animals , Drug Discovery , Drug Evaluation, Preclinical , Humans , Inhibitory Concentration 50 , MAP Kinase Kinase Kinases/metabolism , Microsomes, Liver , Molecular Targeted Therapy , Monocytes , Neoplasms/drug therapy , Phosphorylation , Protein Binding , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Proto-Oncogene Proteins/metabolism , Pyrimidines/chemistry , Rats , Structure-Activity Relationship , Substrate SpecificityABSTRACT
Synthesis, modeling and structure-activity relationship of indazoles as inhibitors of Tpl2 kinase are described. From a high throughput screening effort, we identified an indazole hit compound 5 that has a single digit micromolar Tpl2 activity. Through SAR modifications at the C3 and C5 positions of the indazole, we discovered compound 31 with good potency in LANCE assay and cell-based p-Erk assay.
Subject(s)
Drug Discovery , Enzyme Inhibitors/pharmacology , Indazoles/pharmacology , MAP Kinase Kinase Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Indazoles/chemical synthesis , Indazoles/chemistry , MAP Kinase Kinase Kinases/metabolism , Models, Molecular , Molecular Structure , Monocytes/enzymology , Monocytes/metabolism , Proto-Oncogene Proteins/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Cortisol and the glucocorticoid receptor signaling pathway have been implicated in the development of diabetes and obesity. The reduction of cortisone to cortisol is catalyzed by 11beta-hydroxysteroid dehydrogenase type I (11beta-HSD1). 2,4-Disubsituted benzenesulfonamides were identified as potent inhibitors of both the human and mouse enzymes. The lead compounds displayed good pharmacokinetics and ex vivo inhibition of the target in mice. Cocrystal structures of compounds 1 and 20 bound to human 11beta-HSD1 were obtained. Compound 20 was found to achieve high concentrations in target tissues, resulting in 95% inhibition in the ex vivo assay when dosed with a food mix (0.5 mg of drug per g of food) after 4 days. Compound 20 was efficacious in a mouse diet-induced obesity model and significantly reduced fed glucose and fasted insulin levels. Our findings suggest that 11beta-HSD1 inhibition may be a valid target for the treatment of diabetes.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Diet/adverse effects , Enzyme Inhibitors/pharmacology , Obesity/enzymology , Obesity/etiology , 11-beta-Hydroxysteroid Dehydrogenase Type 1/chemistry , Animals , CHO Cells , Cricetinae , Cricetulus , Crystallography, X-Ray , Disease Models, Animal , Drug Design , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/therapeutic use , Humans , Inhibitory Concentration 50 , Male , Mice , Mice, Inbred C57BL , Models, Molecular , Molecular Conformation , Obesity/drug therapy , 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/pharmacologySubject(s)
Arginine/chemistry , Enzyme Inhibitors/chemistry , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Protein Tyrosine Phosphatase, Non-Receptor Type 1/chemistry , Crystallography, X-Ray , Drug Design , Enzyme Inhibitors/pharmacology , Protein Tyrosine Phosphatase, Non-Receptor Type 1/pharmacology , Structure-Activity RelationshipABSTRACT
11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is the enzyme that converts cortisone to cortisol. Evidence suggests that selective inhibition of 11beta-HSD1 could treat diabetes and metabolic syndrome. Presented herein are the synthesis, structure-activity relationship, and in vivo evaluation of piperazine sulfonamides as 11beta-HSD1 inhibitors. Through modification of our initial lead 5a, we have identified potent and selective 11beta-HSD1 inhibitors such as 13q and 13u with good pharmacokinetic properties.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Disease Models, Animal , Enzyme Inhibitors/pharmacology , Hyperinsulinism/drug therapy , Piperazines/pharmacology , Sulfonamides/pharmacology , Administration, Oral , Animals , Biological Availability , Cortisone/pharmacology , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/therapeutic use , Hyperinsulinism/chemically induced , Hyperinsulinism/enzymology , Piperazines/administration & dosage , Piperazines/pharmacokinetics , Piperazines/therapeutic use , Rats , Sulfonamides/administration & dosage , Sulfonamides/pharmacokinetics , Sulfonamides/therapeutic useABSTRACT
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
The design, synthesis, and biological evaluation of beta-keto sulfones as 11beta-HSD1 inhibitors and the mechanism of inhibition are described here. This class of compounds is not active against 11beta-HSD2 and therefore may have therapeutic potential for metabolic syndrome and type 2 diabetes.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Ketones/chemical synthesis , Ketones/pharmacology , Sulfones/chemical synthesis , Sulfones/pharmacology , Alkylation , Animals , CHO Cells , Cricetinae , Cricetulus , Electrochemistry , Indicators and Reagents , Solvents , 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 design, synthesis, and biological evaluation of arylsulfonamidooxazoles as 11beta-HSD1 inhibitors and the serendipitous discovery of beta-keto sulfones as potent 11beta-HSD1 inhibitors are described here. These two classes of compounds are not active against 11beta-HSD2 and therefore may have significant therapeutic potential for metabolic syndrome, type 2 diabetes and related metabolic dysfunctions.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Oxazoles/pharmacology , Sulfones/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Oxazoles/chemical synthesis , Oxazoles/chemistry , Structure-Activity Relationship , Sulfones/chemical synthesis , Sulfones/chemistryABSTRACT
Copper(II) complexation by a series of ligands containing two 1,4,7-triazacyclononane, [9]aneN(3), groups conjoined by polymethylene chains two to six carbons in length is described. Equilibrium modeling studies in aqueous solution using pH-potentiometry indicate that the smallest homologue of the series, EM2, forms only Cu(EM2)(2+) in dilute aqueous solutions. All other ligands of the series form stable 1:1 (protonated and nonprotonated) and 2:1 dicopper(II) (hydroxo and non-hydroxo) complexes. Those ligands that contain bridging chains of four or more carbon atoms likely form dimeric or oligomeric complex species in solution. The EM ligands with the shortest polymethylene bridging groups form the most stable 1:1 species. There is little difference among the ligands (n = 3-6) in complex stability of the protonated, CuH(2)(EMn)(4+), and dicopper(II), Cu(2)(EMn)(4+), species. UV-vis spectroscopic continuous variation studies at pH 4.0 and 7.5 are interpreted on the basis of the principal equilibrium species obtained from the equilibrium models. Single-crystal X-ray diffraction studies on four complexes ([Cu(EM2)]SO(4).6H(2)O (1), [Cu(2)(EM2)Cl(4)].2H(2)O (2), [Cu(2)(EM6)Cl(4) ] (3), and [Cu(EM3)][ZnBr(4)].H(2)O (4)) characterize structural features of several 1:1 monomeric and dicopper(II) complexes in the crystalline solid. The monomeric compounds contain CuN(6) chromophores while the dicopper(II) compounds contain square pyramidal CuN(3)Cl(2) coordination geometry. Compound 1 crystallizes in space group P&onemacr; with a = 7.849(2) Å, b = 9.783(2) Å, c = 16.919(5) Å, alpha = 78.42(3) degrees, beta = 85.76(3) degrees, gamma = 73.06(3) degrees, and Z = 2. 2: P2(1)/n with a = 9.689(3) Å, b = 11.733(3) Å, c = 10.124(3) Å, beta = 98.20(2) degrees, and Z = 2. 3: P2(1)/n with a = 7.278(2) Å, b = 12.416(3) Å, c = 13.781(2) Å, beta = 90.15(2) degrees, and Z = 2. 4: P2(1)/c with a = 9.295(3) Å, b = 16.233(4) Å, c = 16.544(5) Å, beta = 92.62(2) degrees, and Z = 4. Cyclic voltammograms of aqueous solutions prepared by dissolving [Cu(2)(EM2)Cl(4)].2H(2)O confirm its dissociation to Cu(EM2)(2+). Aqueous solutions containing 1:1 molar ratios of Cu(II) and EM2 in 0.1 mol dm(-)(3) KCl at 25 degrees C show a one-electron chemically reversible reduction at scan rates of 500 mV s(-)(1) with E(1/2) (Cu(II)-Cu(I)) = -868 mV relative to SCE. EPR (X- and Q- band) spectra of frozen solutions (1:1 DMSO/H(2)O and glycerol/H(2)O) of Cu(EM2)(2+) at 100 K are typical of axial copper(II) features (X-band parameters: g( parallel) =2.225 (A( parallel) = 164 x 10(-)(4)) and g( perpendicular) = 2.045).
