ABSTRACT
The transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is a nonselective cation channel that can be activated by a wide range of noxious stimuli, including capsaicin, acid, and heat. Blockade of TRPV1 activation by selective antagonists is under investigation in an attempt to identify novel agents for pain treatment. The design and synthesis of a series of novel TRPV1 antagonists with a variety of different 6,6-heterocyclic cores is described, and an extensive evaluation of the pharmacological and pharmacokinetic properties of a number of these compounds is reported. For example, the 1,8-naphthyridine 52 was characterized as an orally bioavailable and brain penetrant TRPV1 antagonist. In vivo, 52 fully reversed carrageenan-induced thermal hyperalgesia (CITH) in rats and dose-dependently potently reduced complete Freund's adjuvant (CFA) induced chronic inflammatory pain after oral administration.
Subject(s)
Analgesics/chemical synthesis , Naphthyridines/chemical synthesis , Pyrazines/chemical synthesis , Pyridines/chemical synthesis , Pyrimidines/chemical synthesis , TRPV Cation Channels/antagonists & inhibitors , Analgesics/chemistry , Analgesics/pharmacology , Animals , Biological Availability , COS Cells , Capsaicin/pharmacology , Chlorocebus aethiops , Hot Temperature , Humans , Hyperalgesia/drug therapy , In Vitro Techniques , Inflammation/drug therapy , Microsomes, Liver , Naphthyridines/chemistry , Naphthyridines/pharmacology , Pain/drug therapy , Pyrazines/chemistry , Pyrazines/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Quinazolines/chemical synthesis , Quinazolines/chemistry , Quinazolines/pharmacology , Quinolines/chemical synthesis , Quinolines/chemistry , Quinolines/pharmacology , Rats , Structure-Activity Relationship , TRPV Cation Channels/agonistsABSTRACT
Introduction of selected amine containing side chains into the 3-position of N',2-diphenylquinoline-4-carbohydrazide based NK3 antagonists abolishes unwanted hPXR activation. Introduction of a fluorine at the 8-position is necessary to minimize unwanted hI(Kr) affinity and a piperazine N-tert-butyl group is necessary for metabolic stability. The lead compound (8m) occupies receptors within the CNS following oral dosing (Occ(90) 7 mg/kg po; plasma Occ(90) 0.4 microM) and has good selectivity and excellent PK properties.
Subject(s)
Fluorine/chemistry , Hydrazines/chemistry , Neurotransmitter Agents/pharmacology , Piperazines/chemistry , Quinolines/chemistry , Receptors, Neurokinin-3/antagonists & inhibitors , Administration, Oral , Animals , CHO Cells , Cricetinae , Dose-Response Relationship, Drug , Fluorine/pharmacology , Hydrazines/pharmacology , Piperazines/pharmacology , Quinolines/pharmacology , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
A new class of potent NK3R antagonists based on the N',2-diphenylquinoline-4-carbohydrazide core is described. In an ex vivo assay in gerbil, the lead compound 2g occupies receptors within the CNS following oral dosing (Occ(90) 30 mg/kg po; plasma Occ(90) 0.95 microM) and has good selectivity and promising PK properties.
Subject(s)
Hydrazines/chemistry , Hydrazines/pharmacology , Neurotransmitter Agents/chemistry , Neurotransmitter Agents/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Receptors, Neurokinin-3/antagonists & inhibitors , Administration, Oral , Animals , CHO Cells , Cricetinae , Dose-Response Relationship, Drug , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
A new class of high affinity hNK1R antagonists based on seven-membered ring cores has been identified. This series, with relatively simple, compact structures, includes compounds with high affinity, good selectivity, and promising in vivo properties.
Subject(s)
Lactams/chemistry , Neurokinin-1 Receptor Antagonists , Cell Line , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
The synthesis and structure-activity relationships of novel series of alpha-aryloxyphenylacetic acids as PPARalpha/gamma dual agonists are reported. The initial search for surrogates of the ester group in the screen lead led first to the optimization of a subseries with a ketone moiety. Further efforts to modify the ketone subseries led to the design and synthesis of two new subseries containing fused heterocyclic ring systems. All these analogues were characterized by their "super" PPARalpha agonist activity and weak or partial agonist activity on PPARgamma in PPAR-GAL4 transactivation assays despite their similar binding affinities for both receptors. The cocrystal structures of compounds 7 and rosiglitazone with PPARgamma-LBD were compared, and significant differences were found in their interactions with the receptor. Select analogues in each subseries were further evaluated for in vivo efficacy. They all showed excellent anti-hyperglycemic efficacy in a db/db mouse model and hypolipidemic activity in hamster and dog models without provoking the typical PPARgamma-associated side effects in the rat tolerability assay.
Subject(s)
Hypoglycemic Agents/chemical synthesis , Hypolipidemic Agents/chemical synthesis , PPAR alpha/agonists , PPAR delta/agonists , Phenylacetates/chemical synthesis , Animals , Cricetinae , Crystallography, X-Ray , Diabetes Mellitus, Type 2/drug therapy , Dogs , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/pharmacology , Hypolipidemic Agents/chemistry , Hypolipidemic Agents/pharmacokinetics , Hypolipidemic Agents/pharmacology , Kinetics , Male , Mesocricetus , Mice , Mice, Inbred C57BL , Models, Animal , Models, Molecular , Molecular Structure , Phenylacetates/chemistry , Phenylacetates/pharmacokinetics , Phenylacetates/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
A series of metabolically robust N-benzyl-indole selective PPARgamma modulators with either a 3-benzoyl or 3-benzisoxazoyl moiety have been identified. In vitro, these compounds are partial agonists and exhibit reduced adipogenesis in human adipocytes. In vivo, these SPPARgammaMs result in potent glucose lowering in db/db mice and attenuate increases in heart weight and brown adipose tissue that is typically observed in rats upon treatment with PPARgamma full agonists.
Subject(s)
Indoles/pharmacology , PPAR gamma/drug effects , Animals , Area Under Curve , Blood Glucose/metabolism , Humans , Indoles/chemistry , Indoles/pharmacokinetics , Mice , RatsABSTRACT
Liver X receptors are nuclear receptors that regulate metabolism of cholesterol. They are activated by oxysterols resulting in increased transcription of the ABCA1 gene, promoting cholesterol efflux and HDL formation. We have identified podocarpic acid anhydride as a 1nM agonist of LXRalpha and beta receptors. Functionally this agonist was over 8-10-fold better activator of LXR receptors compared to one of the natural ligands, 22-(R)-hydroxy cholesterol, in HEK-293 cells. An imide analog increased the level of HDL by 26%, decreased LDL by 10.6%, and increased triglyceride by 51% in hamsters. Discovery, synthesis, SAR and details of the activities of dimers have been described.
Subject(s)
Abietanes/pharmacology , Cholesterol, HDL/blood , Phenanthrenes/pharmacology , Receptors, Cytoplasmic and Nuclear/agonists , Abietanes/chemistry , Abietanes/pharmacokinetics , Animals , Area Under Curve , Biotransformation , Cell Line , Cricetinae , Dimerization , Humans , Male , Mice , Phenanthrenes/chemistry , Phenanthrenes/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
A series of 2-aryloxy-2-methyl-propionic acid compounds and related analogues were designed, synthesized, and evaluated for their PPAR agonist activities. 2-[(5,7-Dipropyl-3-trifluoromethyl)-benzisoxazol-6-yloxy]-2-methylpropionic acid (4) was identified as a PPARalpha/gamma dual agonist with relative PPARalpha selectivity and demonstrated potent efficacy in lowering both glucose and lipids in animal models without causing body weight gain. The PPARalpha activity of 4 appeared to have played a significant role in lowering glucose levels in db/db mice.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Hyperlipidemias/drug therapy , Hypoglycemic Agents/chemical synthesis , Hypolipidemic Agents/chemical synthesis , Isoxazoles/chemical synthesis , PPAR alpha/agonists , PPAR gamma/agonists , Propionates/chemical synthesis , 3T3-L1 Cells , Animals , Blood Glucose/drug effects , COS Cells , Carrier Proteins/biosynthesis , Carrier Proteins/genetics , Chlorocebus aethiops , Cholesterol/blood , Dogs , Fatty Acid-Binding Proteins , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Hypolipidemic Agents/chemistry , Hypolipidemic Agents/pharmacology , Isoxazoles/chemistry , Isoxazoles/pharmacology , Mice , Mice, Obese , Propionates/chemistry , Propionates/pharmacology , RNA, Messenger/biosynthesis , Radioligand Assay , Structure-Activity Relationship , Transcriptional Activation , Triglycerides/blood , Weight GainABSTRACT
Routine screening for human PPAR ligands yielded compounds 1 and 2, both of which were sub-micromolar hPPARgamma agonists. Synthetic modifications of these leads led to a series of potent substituted 3-benzyl-2-methyl indoles, a subset of which were noted to be selective PPARgamma modulators (SPPARgammaMs). SPPARgammaM 24 displayed robust anti-diabetic activity with an improved therapeutic window in comparison to a PPARgamma full agonist in a rodent efficacy model.
Subject(s)
Inflammation Mediators/metabolism , PPAR gamma/agonists , Animals , Benzoates/chemical synthesis , Benzoates/pharmacology , Benzoates/therapeutic use , Diabetes Mellitus/drug therapy , Disease Models, Animal , Humans , Indoles/chemical synthesis , Indoles/pharmacology , Indoles/therapeutic use , Ligands , Molecular Structure , PPAR gamma/metabolismABSTRACT
A new series of gamma-secretase inhibitors was developed from an in-house screening hit based on a benzobicyclo[4.2.1]nonane core. Lead optimisation studies led to the development of a series of potent inhibitors and in vivo efficacy was demonstrated.
Subject(s)
Alkanes/chemical synthesis , Brain/drug effects , Endopeptidases/metabolism , Heterocyclic Compounds/chemistry , Protease Inhibitors/chemical synthesis , Alkanes/pharmacology , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Amides/chemistry , Amines/chemistry , Amyloid Precursor Protein Secretases , Animals , Aspartic Acid Endopeptidases , Brain/metabolism , Mice , Protease Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
A series of chromane-2-carboxylic acid derivatives was synthesized and evaluated for PPAR agonist activities. A structure-activity relationship was developed toward PPARalpha/gamma dual agonism. As a result, (2R)-7-(3-[2-chloro-4-(4-fluorophenoxy)phenoxy]propoxy)-2-ethylchromane-2-carboxylic acid (48) was identified as a potent, structurally novel, selective PPARalpha/gamma dual agonist. Compound 48 exhibited substantial antihyperglycemic and hypolipidemic activities when orally administered in three different animal models: the db/db mouse type 2 diabetes model, a Syrian hamster lipid model, and a dog lipid model.
Subject(s)
Benzopyrans/chemical synthesis , Chromans/chemical synthesis , Hypoglycemic Agents/chemical synthesis , Hypolipidemic Agents/chemical synthesis , Phenyl Ethers/chemical synthesis , Receptors, Cytoplasmic and Nuclear/agonists , Transcription Factors/agonists , Animals , Benzopyrans/chemistry , Benzopyrans/pharmacokinetics , Benzopyrans/pharmacology , Chromans/chemistry , Chromans/pharmacokinetics , Chromans/pharmacology , Cricetinae , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/genetics , Dogs , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/pharmacology , Hypolipidemic Agents/chemistry , Hypolipidemic Agents/pharmacokinetics , Hypolipidemic Agents/pharmacology , Macaca mulatta , Male , Mesocricetus , Mice , Phenyl Ethers/chemistry , Phenyl Ethers/pharmacokinetics , Phenyl Ethers/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Cytoplasmic and Nuclear/genetics , Receptors, Cytoplasmic and Nuclear/metabolism , Stereoisomerism , Structure-Activity Relationship , Trans-Activators/chemical synthesis , Trans-Activators/chemistry , Trans-Activators/pharmacology , Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
A new class of O-arylmandelic acid PPAR agonists show excellent anti-hyperglycemic efficacy in a db/db mouse model of DM2. These PPARalpha-weighted agonists do not show the typical PPARgamma associated side effects of BAT proliferation and cardiac hypertrophy in a rat tolerability assay.
Subject(s)
Mandelic Acids/pharmacology , Receptors, Cytoplasmic and Nuclear/agonists , Transcription Factors/agonists , Animals , Mandelic Acids/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic , Protein Binding/drug effects , Protein Binding/physiology , Rats , Receptors, Cytoplasmic and Nuclear/metabolism , Transcription Factors/metabolismABSTRACT
A series of amphipathic 3-phenylbenzisoxazoles were found to be potent agonists of human PPARalpha, gamma and delta. The optimization of acid proximal structure for in vitro and in vivo potency is described. Results of po dosed efficacy studies in the db/db mouse model of type 2 diabetes showed efficacy equal or superior to Rosiglitazone in correcting hyperglycemia and hypertriglyceridemia. Good functional receptor selectivity for PPARalpha and gamma over PPARdelta can be obtained.
Subject(s)
Isoxazoles/chemistry , Isoxazoles/pharmacology , Receptors, Cytoplasmic and Nuclear/agonists , Thiazolidinediones , Transcription Factors/agonists , Administration, Oral , Animals , Biological Availability , COS Cells , Diabetes Mellitus, Type 2/drug therapy , Disease Models, Animal , Humans , Isoxazoles/pharmacokinetics , Mice , Mice, Mutant Strains , Nuclear Proteins/agonists , Nuclear Proteins/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Rosiglitazone , Thiazoles/pharmacokinetics , Thiazoles/pharmacology , Transcription Factors/metabolismABSTRACT
We have synthesized iodinated resiniferatoxin bearing a 4-hydroxy-5-iodo-3-methoxyphenylacetate ester (I-RTX) and have characterized its activity on rat and human TRPV1 (VR1) receptors, as well as in behavioral assays of nociception. In whole cell patch-clamp recordings from transfected cells the functional activity of I-RTX was determined. Currents activated by capsaicin exhibited characteristic outward rectification and were antagonized by capsazepine and I-RTX. On rat TRPV1 the affinity of I-RTX was 800-fold higher than that of capsazepine (IC50 = 0.7 and 562 nM, respectively) and 10-fold higher on rat versus human receptors (IC50 = 0.7 and 5.4 nM, respectively). The same difference was observed when comparing the inhibition of [3H]RTX binding to rat and human TRPV1 membranes for both RTX and I-RTX. Additional pharmacological differences were revealed using protons as the stimulus. Under these conditions capsazepine only partly blocked currents through rat TRPV1 receptors (by 70 to 80% block), yet was a full antagonist on human receptors. In contrast, I-RTX completely blocked proton-induced currents in both species and that activated by noxious heat. I-RTX also blocked capsaicin-induced firing of C-fibers in a rat in vitro skin-nerve assay. Despite this activity and the high affinity of I-RTX for rat TRPV1, only capsazepine proved to be an effective antagonist of capsaicin-induced paw flinching in rats. Thus, although I-RTX has limited utility for in vivo behavioral studies it is a high-affinity TRPV1 receptor antagonist that will be useful to characterize the functional properties of cloned and native vanilloid receptor subtypes in vitro.
Subject(s)
Action Potentials/drug effects , Capsaicin/metabolism , Diterpenes/pharmacology , Receptors, Drug/antagonists & inhibitors , Receptors, Drug/deficiency , Action Potentials/physiology , Animals , CHO Cells , Cannabinoids/antagonists & inhibitors , Cannabinoids/genetics , Capsaicin/pharmacology , Cricetinae , Dose-Response Relationship, Drug , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Rats , Rats, Sprague-Dawley , Receptors, Drug/geneticsABSTRACT
Insulin regulates cellular metabolism and growth through activation of insulin receptors (IRs). We recently identified a non-peptide small-molecule IR activator (compound 2), which induced human IR tyrosine kinase activity in Chinese-hamster ovary cells expressing human IR [Qureshi, Ding, Li, Szalkowski, Biazzo-Ashnault, Xie, Saperstein, Brady, Huskey, Shen et al. (2000) J. Biol. Chem. 275, 36590-36595]. Oral treatment with this compound resulted in correction of hyperglycaemia, hypertriacylglycerolaemia and hyperinsulinaemia in several rodent models of diabetes. In the present study, we have found that this compound increased tyrosine phosphorylation of the IR beta-subunit and IR substrate 1 in primary rat adipocytes as well as induced phosphorylation of Akt, the 70 kDa ribosomal protein S6 kinase and glycogen synthase-3 (deactivation) in Chinese-hamster ovary cells expressing human IR. Similar to insulin, compound 2 stimulated glucose uptake, glycogen synthesis and inhibited isoprenaline-stimulated lipolysis in adipocytes. A structurally related analogue (compound 3) was devoid of the above activities suggesting that the activity of compound 2 is specifically mediated by targeted IR activation. The effects of compound 2 on stimulation of glucose uptake, glycogen synthesis and inhibition of lipolysis were blocked by wortmannin, consistent with the involvement of a phosphoinositide 3-kinase-dependent pathway. In addition, compound 2, but not compound 3, exhibited additive or synergistic effects with sub-maximal concentrations of insulin in rat adipocytes. Thus the IR activator was capable of activating insulin-mediated signalling and metabolic pathways in primary adipocytes. These results demonstrate that IR activators have implications for the future development of new therapeutic approaches to Type I and Type II diabetes.
Subject(s)
Insulin/metabolism , Receptor, Insulin/metabolism , Signal Transduction , Adipocytes/metabolism , Androstadienes/pharmacology , Animals , Blotting, Western , CHO Cells , Cricetinae , Enzyme Inhibitors/pharmacology , Glucose/metabolism , Glycerol/metabolism , Glycogen Synthase/metabolism , Humans , Isoproterenol/pharmacology , Male , Phosphorylation , Rats , Rats, Wistar , Ribosomal Protein S6 Kinases/metabolism , WortmanninABSTRACT
The LXR nuclear receptors are intracellular sensors of cholesterol excess and are activated by various oxysterols. LXRs have been shown to regulate multiple genes of lipid metabolism, including ABCA1 (formerly known as ABC1). ABCA1 is a lipid pump that effluxes cholesterol and phospholipid out of cells. ABCA1 deficiency causes extremely low high density lipoprotein (HDL) levels, demonstrating the importance of ABCA1 in the formation of HDL. The present work shows that the acetyl-podocarpic dimer (APD) is a potent, selective agonist for both LXRalpha (NR1H3) and LXRbeta (NR1H2). In transient transactivation assays, APD was approximately 1000-fold more potent, and yielded approximately 6-fold greater maximal stimulation, than the widely used LXR agonist 22-(R)-hydroxycholesterol. APD induced ABCA1 mRNA levels, and increased efflux of both cholesterol and phospholipid, from multiple cell types. Gas chromatography-mass spectrometry measurements demonstrated that APD stimulated efflux of endogenous cholesterol, eliminating any possible artifacts of cholesterol labeling. For both mRNA induction and stimulation of cholesterol efflux, APD was found to be more effective than was cholesterol loading. Taken together, these data show that APD is a more effective LXR agonist than endogenous oxysterols. LXR agonists may therefore be useful for the prevention and treatment of atherosclerosis, especially in the context of low HDL levels.