RESUMO
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.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hiperlipidemias/tratamento farmacológico , Hipoglicemiantes/síntese química , Hipolipemiantes/síntese química , Isoxazóis/síntese química , PPAR alfa/agonistas , PPAR gama/agonistas , Propionatos/síntese química , Células 3T3-L1 , Animais , Glicemia/efeitos dos fármacos , Células COS , Proteínas de Transporte/biossíntese , Proteínas de Transporte/genética , Chlorocebus aethiops , Colesterol/sangue , Cães , Proteínas de Ligação a Ácido Graxo , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Isoxazóis/química , Isoxazóis/farmacologia , Camundongos , Camundongos Obesos , Propionatos/química , Propionatos/farmacologia , RNA Mensageiro/biossíntese , Ensaio Radioligante , Relação Estrutura-Atividade , Ativação Transcricional , Triglicerídeos/sangue , Aumento de PesoRESUMO
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.
Assuntos
Hipoglicemiantes/síntese química , Hipolipemiantes/síntese química , PPAR alfa/agonistas , PPAR delta/agonistas , Fenilacetatos/síntese química , Animais , Cricetinae , Cristalografia por Raios X , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cães , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Hipolipemiantes/química , Hipolipemiantes/farmacocinética , Hipolipemiantes/farmacologia , Cinética , Masculino , Mesocricetus , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Modelos Moleculares , Estrutura Molecular , Fenilacetatos/química , Fenilacetatos/farmacocinética , Fenilacetatos/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Benzopiranos/síntese química , Cromanos/síntese química , Hipoglicemiantes/síntese química , Hipolipemiantes/síntese química , Éteres Fenílicos/síntese química , Receptores Citoplasmáticos e Nucleares/agonistas , Fatores de Transcrição/agonistas , Animais , Benzopiranos/química , Benzopiranos/farmacocinética , Benzopiranos/farmacologia , Cromanos/química , Cromanos/farmacocinética , Cromanos/farmacologia , Cricetinae , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Cães , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Hipolipemiantes/química , Hipolipemiantes/farmacocinética , Hipolipemiantes/farmacologia , Macaca mulatta , Masculino , Mesocricetus , Camundongos , Éteres Fenílicos/química , Éteres Fenílicos/farmacocinética , Éteres Fenílicos/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Transativadores/síntese química , Transativadores/química , Transativadores/farmacologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
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.
Assuntos
Analgésicos/síntese química , Naftiridinas/síntese química , Pirazinas/síntese química , Piridinas/síntese química , Pirimidinas/síntese química , Canais de Cátion TRPV/antagonistas & inibidores , Analgésicos/química , Analgésicos/farmacologia , Animais , Disponibilidade Biológica , Células COS , Capsaicina/farmacologia , Chlorocebus aethiops , Temperatura Alta , Humanos , Hiperalgesia/tratamento farmacológico , Técnicas In Vitro , Inflamação/tratamento farmacológico , Microssomos Hepáticos , Naftiridinas/química , Naftiridinas/farmacologia , Dor/tratamento farmacológico , Pirazinas/química , Pirazinas/farmacologia , Piridinas/química , Piridinas/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Quinazolinas/síntese química , Quinazolinas/química , Quinazolinas/farmacologia , Quinolinas/síntese química , Quinolinas/química , Quinolinas/farmacologia , Ratos , Relação Estrutura-Atividade , Canais de Cátion TRPV/agonistasRESUMO
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.
Assuntos
Lactamas/química , Antagonistas dos Receptores de Neurocinina-1 , Linhagem Celular , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Flúor/química , Hidrazinas/química , Neurotransmissores/farmacologia , Piperazinas/química , Quinolinas/química , Receptores da Neurocinina-3/antagonistas & inibidores , Administração Oral , Animais , Células CHO , Cricetinae , Relação Dose-Resposta a Droga , Flúor/farmacologia , Hidrazinas/farmacologia , Piperazinas/farmacologia , Quinolinas/farmacologia , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
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.
Assuntos
Hidrazinas/química , Hidrazinas/farmacologia , Neurotransmissores/química , Neurotransmissores/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Receptores da Neurocinina-3/antagonistas & inibidores , Administração Oral , Animais , Células CHO , Cricetinae , Relação Dose-Resposta a Droga , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
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.
Assuntos
Mediadores da Inflamação/metabolismo , PPAR gama/agonistas , Animais , Benzoatos/síntese química , Benzoatos/farmacologia , Benzoatos/uso terapêutico , Diabetes Mellitus/tratamento farmacológico , Modelos Animais de Doenças , Humanos , Indóis/síntese química , Indóis/farmacologia , Indóis/uso terapêutico , Ligantes , Estrutura Molecular , PPAR gama/metabolismoRESUMO
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.
Assuntos
Alcanos/síntese química , Encéfalo/efeitos dos fármacos , Endopeptidases/metabolismo , Compostos Heterocíclicos/química , Inibidores de Proteases/síntese química , Alcanos/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Amidas/química , Aminas/química , Secretases da Proteína Precursora do Amiloide , Animais , Ácido Aspártico Endopeptidases , Encéfalo/metabolismo , Camundongos , Inibidores de Proteases/farmacologia , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Abietanos/farmacologia , HDL-Colesterol/sangue , Fenantrenos/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Abietanos/química , Abietanos/farmacocinética , Animais , Área Sob a Curva , Biotransformação , Linhagem Celular , Cricetinae , Dimerização , Humanos , Masculino , Camundongos , Fenantrenos/química , Fenantrenos/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Indóis/farmacologia , PPAR gama/efeitos dos fármacos , Animais , Área Sob a Curva , Glicemia/metabolismo , Humanos , Indóis/química , Indóis/farmacocinética , Camundongos , RatosRESUMO
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.
Assuntos
Isoxazóis/química , Isoxazóis/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Tiazolidinedionas , Fatores de Transcrição/agonistas , Administração Oral , Animais , Disponibilidade Biológica , Células COS , Diabetes Mellitus Tipo 2/tratamento farmacológico , Modelos Animais de Doenças , Humanos , Isoxazóis/farmacocinética , Camundongos , Camundongos Mutantes , Proteínas Nucleares/agonistas , Proteínas Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Rosiglitazona , Tiazóis/farmacocinética , Tiazóis/farmacologia , Fatores de Transcrição/metabolismoRESUMO
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.
Assuntos
Ácidos Mandélicos/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Fatores de Transcrição/agonistas , Animais , Ácidos Mandélicos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Ratos , Receptores Citoplasmáticos e Nucleares/metabolismo , Fatores de Transcrição/metabolismoRESUMO
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.
Assuntos
Insulina/metabolismo , Receptor de Insulina/metabolismo , Transdução de Sinais , Adipócitos/metabolismo , Androstadienos/farmacologia , Animais , Western Blotting , Células CHO , Cricetinae , Inibidores Enzimáticos/farmacologia , Glucose/metabolismo , Glicerol/metabolismo , Glicogênio Sintase/metabolismo , Humanos , Isoproterenol/farmacologia , Masculino , Fosforilação , Ratos , Ratos Wistar , Proteínas Quinases S6 Ribossômicas/metabolismo , WortmaninaRESUMO
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.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Capsaicina/metabolismo , Diterpenos/farmacologia , Receptores de Droga/antagonistas & inibidores , Receptores de Droga/deficiência , Potenciais de Ação/fisiologia , Animais , Células CHO , Canabinoides/antagonistas & inibidores , Canabinoides/genética , Capsaicina/farmacologia , Cricetinae , Relação Dose-Resposta a Droga , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ratos , Ratos Sprague-Dawley , Receptores de Droga/genéticaRESUMO
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.