ABSTRACT
µ-Opioid receptor (MOR) agonism induces palatable food consumption principally through modulation of the rewarding properties of food. N-{[3,5-difluoro-3'-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine (GSK1521498) is a novel opioid receptor inverse agonist that, on the basis of in vitro affinity assays, is greater than 10- or 50-fold selective for human or rat MOR, respectively, compared with κ-opioid receptors (KOR) and δ-opioid receptors (DOR). Likewise, preferential MOR occupancy versus KOR and DOR was observed by autoradiography in brain slices from Long Evans rats dosed orally with the drug. GSK1521498 suppressed nocturnal food consumption of standard or palatable chow in lean and diet-induced obese (DIO) Long Evans rats. Both the dose-response relationship and time course of efficacy in lean rats fed palatable chow correlated with µ receptor occupancy and the plasma concentration profile of the drug. Chronic oral administration of GSK1521498 induced body weight loss in DIO rats, which comprised fat mass reduction. The reduction in body weight was equivalent to the cumulative reduction in food consumption; thus, the effect of GSK1521498 on body weight is related to inhibition of food consumption. GSK1521498 suppressed the preference for sucrose-containing solutions in lean rats. In operant response models also using lean rats, GSK1521498 reduced the reinforcement efficacy of palatable food reward and enhanced satiety. In conclusion, GSK1521498 is a potent, MOR-selective inverse agonist that modulates the hedonic aspects of ingestion and, therefore, could represent a pharmacological treatment for obesity and binge-eating disorders.
Subject(s)
Anti-Obesity Agents/pharmacology , Drinking Behavior/drug effects , Feeding Behavior/drug effects , Indans/pharmacology , Receptors, Opioid, mu/agonists , Triazoles/pharmacology , Adiposity/drug effects , Animals , Anti-Obesity Agents/pharmacokinetics , Body Weight/drug effects , Brain/metabolism , Calibration , Conditioning, Operant/drug effects , Data Interpretation, Statistical , Food Preferences/drug effects , Guanosine 5'-O-(3-Thiotriphosphate)/pharmacology , Indans/pharmacokinetics , Injections, Intravenous , Male , Rats , Rats, Sprague-Dawley , Receptors, Opioid, delta/metabolism , Receptors, Opioid, kappa/metabolism , Satiety Response/drug effects , Triazoles/pharmacokinetics , Weight Loss/drug effectsABSTRACT
A series of phenoxyacetic acids as subtype selective and potent hPPARδ partial agonists is described. Many analogues were readily accessible via a single solution-phase synthetic route which resulted in the rapid identification of key structure-activity relationships (SAR), and the discovery of two potent exemplars which were further evaluated in vivo. Details of the SAR, optimization, and in vivo efficacy of this series are presented herein.
Subject(s)
Acetates/chemistry , PPAR delta/agonists , Acetates/chemical synthesis , Acetates/pharmacokinetics , Animals , Binding Sites , Crystallography, X-Ray , Humans , Male , Mice , Microsomes, Liver/metabolism , PPAR delta/metabolism , Rats , Structure-Activity RelationshipABSTRACT
Opioid receptors play an important role in both behavioral and homeostatic functions. We herein report tetrahydroquinoline derivatives as opioid receptor antagonists. SAR studies led to the identification of the potent antagonist 2v, endowed with 1.58nM (K(i)) functional activity against the µ opioid receptor. DMPK data suggest that novel tetrahydroquinoline analogs may be advantageous in peripheral applications.
Subject(s)
Narcotic Antagonists , Quinolines/chemistry , Quinolines/pharmacology , Receptors, Opioid/metabolism , Animals , CHO Cells , Cricetinae , Cricetulus , Humans , Quinolines/pharmacokinetics , Rats , Rats, Long-Evans , Structure-Activity RelationshipABSTRACT
The discovery and development of a series of thiophenes as potent and selective inhibitors of PLK is described. Identification and characterization of 2, a useful in vitro PLK inhibitor tool compound, is also presented.
Subject(s)
Cell Cycle Proteins/antagonists & inhibitors , Chemistry, Pharmaceutical/methods , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Thiophenes/antagonists & inhibitors , Animals , Cell Cycle , Cell Cycle Proteins/chemistry , Cell Line, Tumor , Cell Proliferation , Drug Design , Humans , Inhibitory Concentration 50 , Mice , Mitosis , Models, Chemical , Molecular Conformation , Protein Serine-Threonine Kinases/chemistry , Proto-Oncogene Proteins/chemistry , Thiophenes/chemistry , Polo-Like Kinase 1ABSTRACT
A series of pyrazolo[1,5-a]pyridine derivatives was designed and synthesized as novel potent p38 kinase inhibitors. Our approaches towards improving in vitro metabolism and in vivo pharmacokinetic properties of the series are described.
Subject(s)
Chemistry, Pharmaceutical/methods , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Pyridines/chemical synthesis , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacology , Area Under Curve , Dogs , Drug Design , Humans , Inhibitory Concentration 50 , Leukocytes, Mononuclear/drug effects , MAP Kinase Signaling System , Pyridines/pharmacokinetics , Rats , Structure-Activity Relationship , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
Inhibition of the vascular endothelial growth factor (VEGF) signaling pathway has emerged as one of the most promising new approaches for cancer therapy. We describe herein the key steps starting from an initial screening hit leading to the discovery of pazopanib, N(4)-(2,3-dimethyl-2H-indazol-6-yl)-N(4)-methyl-N(2)-(4-methyl-3-sulfonamidophenyl)-2,4-pyrimidinediamine, a potent pan-VEGF receptor (VEGFR) inhibitor under clinical development for renal-cell cancer and other solid tumors.
Subject(s)
Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Sulfonamides/chemistry , Sulfonamides/pharmacology , Animals , Cells, Cultured , Crystallography, X-Ray , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/metabolism , Humans , Indazoles , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Mice , Models, Molecular , Molecular Structure , Neoplasms/blood supply , Neoplasms/drug therapy , Neoplasms/enzymology , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Receptors, Vascular Endothelial Growth Factor/chemistry , Receptors, Vascular Endothelial Growth Factor/metabolism , Sulfonamides/therapeutic use , Xenograft Model Antitumor AssaysABSTRACT
A series of amino acid anthranilamide derivatives identified from a high-throughput screening campaign as novel, potent, and glucose-sensitive inhibitors of human liver glycogen phosphorylase a are described. A solid-phase synthesis using Wang resin was also developed which provided efficient access to a variety of analogues, and resulted in the identification of key structure-activity relationships, and the discovery of a potent exemplar (IC(50)=80 nM). The SAR scope, synthetic strategy, and in vitro results for this series are presented herein.
Subject(s)
Glycogen Phosphorylase, Liver Form/antagonists & inhibitors , ortho-Aminobenzoates/chemistry , Amino Acids/chemistry , Animals , Chemistry, Pharmaceutical/methods , Drug Design , Glycogen Phosphorylase, Liver Form/chemistry , Humans , Inhibitory Concentration 50 , Liver/enzymology , Microsomes, Liver/enzymology , Models, Chemical , Rats , Structure-Activity Relationship , Urea/chemistry , ortho-Aminobenzoates/pharmacologyABSTRACT
With the development of targeted therapeutics, especially for small-molecule inhibitors, it is important to understand whether the observed in vivo efficacy correlates with the modulation of desired/intended target in vivo. We have developed a small-molecule inhibitor of all three vascular endothelial growth factor (VEGF) receptors (VEGFR), platelet-derived growth factor receptor, and c-Kit tyrosine kinases, pazopanib (GW786034), which selectively inhibits VEGF-induced endothelial cell proliferation. It has good oral exposure and inhibits angiogenesis and tumor growth in mice. Because bolus administration of the compound results in large differences in C(max) and C(trough), we investigated the effect of continuous infusion of a VEGFR inhibitor on tumor growth and angiogenesis. GW771806, which has similar enzyme and cellular profiles to GW786034, was used for these studies due to higher solubility requirements for infusion studies. Comparing the pharmacokinetics by two different routes of administration (bolus p.o. dosing and continuous infusion), we showed that the antitumor and antiangiogenic activity of VEGFR inhibitors is dependent on steady-state concentration of the compound above a threshold. The steady-state concentration required for these effects is consistent with the concentration required for the inhibition of VEGF-induced VEGFR2 phosphorylation in mouse lungs. Furthermore, the steady-state concentration of pazopanib determined from preclinical activity showed a strong correlation with the pharmacodynamic effects and antitumor activity in the phase I clinical trial.
Subject(s)
Antineoplastic Agents/pharmacology , Antineoplastic Agents/pharmacokinetics , Indazoles/pharmacology , Indazoles/pharmacokinetics , Neovascularization, Pathologic/pathology , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/pharmacokinetics , Pyrimidines/pharmacology , Pyrimidines/pharmacokinetics , Sulfonamides/pharmacology , Sulfonamides/pharmacokinetics , Sulfones/pharmacology , Sulfones/pharmacokinetics , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/blood , Cell Line, Tumor , Cell-Free System , Cornea/pathology , Dose-Response Relationship, Drug , Female , Fibroblast Growth Factor 2/pharmacology , Humans , Indazoles/administration & dosage , Indazoles/blood , Inhibitory Concentration 50 , Mice , Mice, Nude , Phosphorylation/drug effects , Phosphotyrosine/metabolism , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/blood , Pyrimidines/administration & dosage , Pyrimidines/blood , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Sulfonamides/administration & dosage , Sulfonamides/blood , Sulfones/administration & dosage , Sulfones/blood , Vascular Endothelial Growth Factor A/pharmacologyABSTRACT
A series of derivatives of 2-anilino-5-phenyloxazole (5) has been identified as inhibitors of VEGFR2 kinase. Herein we describe the structure-activity relationship (SAR) of this novel template. Optimization of both aryl rings led to very potent inhibitors at both the enzymatic and cellular levels. Oxazole 39 had excellent solubility and good oral PK when dosed as the bis-mesylate salt and demonstrated moderate in vivo efficacy against HT29 human colon tumor xenografts. X-ray crystallography confirmed the proposed binding mode, and comparison of oxazoles 39 and 46 revealed interesting differences in orientation of 2-pyridyl and 3-pyridyl rings, respectively, attached at the meta position of the 5-phenyl ring.