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1.
J Pharmacol Exp Ther ; 358(3): 371-86, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27411717

RESUMO

To identify novel targets for neuropathic pain, 3097 mouse knockout lines were tested in acute and persistent pain behavior assays. One of the lines from this screen, which contained a null allele of the adapter protein-2 associated kinase 1 (AAK1) gene, had a normal response in acute pain assays (hot plate, phase I formalin), but a markedly reduced response to persistent pain in phase II formalin. AAK1 knockout mice also failed to develop tactile allodynia following the Chung procedure of spinal nerve ligation (SNL). Based on these findings, potent, small-molecule inhibitors of AAK1 were identified. Studies in mice showed that one such inhibitor, LP-935509, caused a reduced pain response in phase II formalin and reversed fully established pain behavior following the SNL procedure. Further studies showed that the inhibitor also reduced evoked pain responses in the rat chronic constriction injury (CCI) model and the rat streptozotocin model of diabetic peripheral neuropathy. Using a nonbrain-penetrant AAK1 inhibitor and local administration of an AAK1 inhibitor, the relevant pool of AAK1 for antineuropathic action was found to be in the spinal cord. Consistent with these results, AAK1 inhibitors dose-dependently reduced the increased spontaneous neural activity in the spinal cord caused by CCI and blocked the development of windup induced by repeated electrical stimulation of the paw. The mechanism of AAK1 antinociception was further investigated with inhibitors of α2 adrenergic and opioid receptors. These studies showed that α2 adrenergic receptor inhibitors, but not opioid receptor inhibitors, not only prevented AAK1 inhibitor antineuropathic action in behavioral assays, but also blocked the AAK1 inhibitor-induced reduction in spinal neural activity in the rat CCI model. Hence, AAK1 inhibitors are a novel therapeutic approach to neuropathic pain with activity in animal models that is mechanistically linked (behaviorally and electrophysiologically) to α2 adrenergic signaling, a pathway known to be antinociceptive in humans.


Assuntos
Neuralgia/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Técnicas de Inativação de Genes , Células HEK293 , Humanos , Masculino , Camundongos , Neuralgia/metabolismo , Neuralgia/fisiopatologia , Nociceptividade/efeitos dos fármacos , Fenótipo , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/genética , Ratos , Medula Espinal/efeitos dos fármacos , Medula Espinal/enzimologia , Medula Espinal/fisiopatologia
2.
ACS Med Chem Lett ; 7(6): 590-4, 2016 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-27326332

RESUMO

BMS-711939 (3) is a potent and selective peroxisome proliferator-activated receptor (PPAR) α agonist, with an EC50 of 4 nM for human PPARα and >1000-fold selectivity vs human PPARγ (EC50 = 4.5 µM) and PPARδ (EC50 > 100 µM) in PPAR-GAL4 transactivation assays. Compound 3 also demonstrated excellent in vivo efficacy and safety profiles in preclinical studies and thus was chosen for further preclinical evaluation. The synthesis, structure-activity relationship (SAR) studies, and in vivo pharmacology of 3 in preclinical animal models as well as its ADME profile are described.

3.
Angiology ; 67(4): 346-9, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26056393

RESUMO

Screening for concomitant atherosclerotic disease is important in cardiovascular risk reduction. This study assessed the prevalence of carotid artery disease (CAD) and peripheral arterial disease (PAD) in patients with known abdominal aortic aneurysms (AAAs). All patients with AAA attending the vascular laboratory between the January 1, 2007, and December 31, 2009, were eligible for a carotid ultrasound and measurement of ankle brachial indices. A total of 389 (305 males) patients were identified on the AAA surveillance program with a mean (±standard deviation) age of 76 (±8) years. The mean age of the males was 75.4 (±7.8) years, and the mean age of the females was 77 (±11) years. A total of 332 patients were assessed for CAD, and 101 (30.4%) of those were found to have significant disease. A total of 289 patients were assessed for PAD of which 131 (45.3%) were found to have PAD at rest, and 289 patients were assessed for both and 59 (20.4%) patients had significant CAD + PAD. Patients with AAAs are at high risk of other atherosclerotic disorders, and, therefore, they should receive intensive medical optimization.


Assuntos
Aneurisma da Aorta Abdominal/diagnóstico , Doenças das Artérias Carótidas/diagnóstico , Doença Arterial Periférica/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Índice Tornozelo-Braço/métodos , Aneurisma da Aorta Abdominal/complicações , Aneurisma da Aorta Abdominal/epidemiologia , Doenças das Artérias Carótidas/complicações , Doenças das Artérias Carótidas/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/complicações , Doença Arterial Periférica/epidemiologia , Prevalência , Fatores de Risco
4.
Malar J ; 14: 324, 2015 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-26289816

RESUMO

BACKGROUND: Emerging resistance of the malaria parasite Plasmodium to current therapies underscores the critical importance of exploring novel strategies for disease eradication. Plasmodium species are obligate intracellular protozoan parasites. They rely on an unusual form of substrate-dependent motility for their migration on and across host-cell membranes and for host cell invasion. This peculiar motility mechanism is driven by the 'glideosome', an actin-myosin associated, macromolecular complex anchored to the inner membrane complex of the parasite. Myosin A, actin, aldolase, and thrombospondin-related anonymous protein (TRAP) constitute the molecular core of the glideosome in the sporozoite, the mosquito stage that brings the infection into mammals. METHODS: Virtual library screening of a large compound library against the PfAldolase-TRAP complex was used to identify candidate compounds that stabilize and prevent the disassembly of the glideosome. The mechanism of these compounds was confirmed by biochemical, biophysical and parasitological methods. RESULTS: A novel inhibitory effect on the parasite was achieved by stabilizing a protein-protein interaction within the glideosome components. Compound 24 disrupts the gliding and invasive capabilities of Plasmodium parasites in in vitro parasite assays. A high-resolution, ternary X-ray crystal structure of PfAldolase-TRAP in complex with compound 24 confirms the mode of interaction and serves as a platform for future ligand optimization. CONCLUSION: This proof-of-concept study presents a novel approach to anti-malarial drug discovery and design. By strengthening a protein-protein interaction within the parasite, an avenue towards inhibiting a previously "undruggable" target is revealed and the motility motor responsible for successful invasion of host cells is rendered inactive. This study provides new insights into the malaria parasite cell invasion machinery and convincingly demonstrates that liver cell invasion is dramatically reduced by 95 % in the presence of the small molecule stabilizer compound 24.


Assuntos
Frutose-Bifosfato Aldolase/metabolismo , Proteínas de Membrana/metabolismo , Complexos Multiproteicos/química , Proteínas de Protozoários/metabolismo , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Frutose-Bifosfato Aldolase/química , Hepatócitos/efeitos dos fármacos , Humanos , Proteínas de Membrana/química , Simulação de Acoplamento Molecular , Complexos Multiproteicos/efeitos dos fármacos , Plasmodium falciparum/química , Estabilidade Proteica/efeitos dos fármacos , Proteínas de Protozoários/química , Coelhos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/toxicidade , Ressonância de Plasmônio de Superfície
5.
Bioorg Med Chem Lett ; 25(6): 1196-205, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25686852

RESUMO

The design, synthesis and structure-activity relationships of a novel series of 3,4-disubstituted pyrrolidine acid analogs as PPAR ligands is outlined. In both the 1,3- and 1,4-oxybenzyl pyrrolidine acid series, the preferred stereochemistry was shown to be the cis-3R,4S isomer, as exemplified by the potent dual PPARα/γ agonists 3k and 4i. The N-4-trifluoromethyl-pyrimidinyl pyrrolidine acid analog 4i was efficacious in lowering fasting glucose and triglyceride levels in diabetic db/db mice.


Assuntos
Hipoglicemiantes/síntese química , PPAR alfa/agonistas , PPAR gama/agonistas , Pirrolidinas/química , Animais , Glicemia/análise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Desenho de Drogas , Feminino , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Ligantes , Camundongos , Camundongos Obesos , PPAR alfa/metabolismo , PPAR gama/metabolismo , Pirrolidinas/síntese química , Pirrolidinas/uso terapêutico , Estereoisomerismo , Relação Estrutura-Atividade , Triglicerídeos/sangue
6.
Neurology ; 82(19): 1693-9, 2014 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-24727313

RESUMO

OBJECTIVE: We hypothesized that serum lipids, which experimental data suggest may be key initiators of carotid plaque inflammation, would be associated with plaque inflammation on (18)fluorodeoxyglucose (FDG)-PET in patients with acutely symptomatic carotid stenosis. METHODS: In this cohort study, consecutive patients with acute symptomatic internal carotid artery (ICA) stenosis (≥50%) underwent carotid PET-CT. We quantified plaque FDG uptake as follows: (1) average maximum standardized uptake values (SUVmax) across 10 regions of interest (ROI); (2) highest single ROI SUV measure (SUVROImax); (3) averaged mean SUV across 10 ROIs (SUVmean). RESULTS: Sixty-one patients were included. Plaque inflammatory FDG SUVmax was associated with increasing tertiles of low-density lipoprotein (LDL) (trend p = 0.004), total cholesterol (p = 0.009), and triglycerides (p = 0.01), and with lower high-density lipoprotein (HDL) (p = 0.005). When analyzed as a continuous variable, LDL was associated with symptomatic ICA SUVmean (Spearman rho 0.44, p = 0.009), SUVROImax (rho 0.33, p = 0.01), and SUVmax (rho 0.35, p = 0.06). Total cholesterol was associated with SUVmean (rho 0.33, p = 0.009), with trends for SUVmax (rho 0.24, p = 0.059) and SUVROImax (rho 0.23, p = 0.08). Triglycerides were associated with SUVmax (rho 0.32, p = 0.01) and SUVROImax (rho 0.35, p = 0.005). HDL was associated with lower SUVmax (rho -0.37, p = 0.004) and SUVROImax (rho -0.44, p = 0.0004). On multivariable linear regression analysis adjusting for age, sex, degree of carotid stenosis, statins, and smoking, LDL (p = 0.008) and total cholesterol (p = 0.04) were independently associated with SUVmax. CONCLUSION: Serum LDL and total cholesterol were associated with acutely symptomatic carotid plaque FDG uptake, supporting experimental data suggesting lipids may promote plaque inflammation, mediating rupture and clinical events.


Assuntos
Estenose das Carótidas/sangue , Colesterol/sangue , Inflamação/sangue , Placa Aterosclerótica/sangue , Triglicerídeos/sangue , Idoso , Idoso de 80 Anos ou mais , Estenose das Carótidas/complicações , Estenose das Carótidas/diagnóstico por imagem , Estenose das Carótidas/patologia , Estudos de Coortes , Feminino , Fluordesoxiglucose F18 , Neuroimagem Funcional , Humanos , Inflamação/complicações , Inflamação/diagnóstico por imagem , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , Placa Aterosclerótica/complicações , Placa Aterosclerótica/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Tomografia Computadorizada por Raios X
7.
Ann Neurol ; 71(5): 709-18, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22461139

RESUMO

OBJECTIVE: Symptomatic carotid stenosis is associated with a 3-fold risk of early stroke recurrence compared to other stroke subtypes. Current carotid imaging techniques rely on estimating plaque-related lumen narrowing but do not evaluate intraplaque inflammation, a key mediator of plaque rupture and thromboembolism. Using combined (18) F-fluorodeoxyglucose positron-emission tomography (FDG-PET)/computed tomography, we investigated the relation between inflammation-related FDG uptake and stroke recurrence. METHODS: Consecutive patients with a recent (median, 6.5 days; interquartile range, 4-8) stroke, transient ischemic attack (TIA), or retinal embolism and ipsilateral carotid stenosis (≥50%) were included. FDG uptake was quantified as mean standardized uptake values (SUVs, g/ml). Patients were followed prospectively for stroke recurrence. RESULTS: Sixty patients were included (25 stroke, 29 TIA, 6 retinal embolism). Twenty-two percent (13 of 60) had stroke recurrence within 90 days. FDG uptake in ipsilateral carotid plaque was greater in patients with early recurrent stroke (mean SUV, 1.85 g/ml; standard deviation [SD], 0.44 vs 1.58 g/ml; SD, 0.32, p = 0.02). On life-table analysis, 90-day recurrence rates with mean SUV greater than a 2.14 g/ml threshold were 80% (95% confidence interval [CI], 41.8-99.2) versus 22.9% (95% CI, 12.3-40.3) with SUV ≤2.14 g/ml (log-rank, p < 0.0001). In a Cox regression model including age and degree of stenosis (50-69% or ≥70%), mean plaque FDG uptake was the only independent predictor of stroke recurrence (adjusted hazard ratio, 6.1; 95% CI, 1.3-28.8; p = 0.02). INTERPRETATION: In recently symptomatic carotid stenosis, inflammation-related FDG uptake was associated with early stroke recurrence, independent of the degree of stenosis. Plaque FDG-PET may identify patients at highest risk for stroke recurrence, who may be selected for immediate revascularization or intensive medical treatment.


Assuntos
Estenose das Carótidas/diagnóstico por imagem , Diagnóstico Precoce , Inflamação/diagnóstico por imagem , Placa Aterosclerótica/diagnóstico por imagem , Acidente Vascular Cerebral/diagnóstico por imagem , Idoso , Estenose das Carótidas/complicações , Feminino , Fluordesoxiglucose F18 , Humanos , Interpretação de Imagem Assistida por Computador , Inflamação/complicações , Masculino , Imagem Multimodal , Placa Aterosclerótica/complicações , Tomografia por Emissão de Pósitrons , Modelos de Riscos Proporcionais , Curva ROC , Compostos Radiofarmacêuticos , Recidiva , Sensibilidade e Especificidade , Acidente Vascular Cerebral/etiologia , Tomografia Computadorizada por Raios X
8.
Invest Ophthalmol Vis Sci ; 52(10): 7548-55, 2011 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-21873671

RESUMO

PURPOSE: Myocilin is thought to be a stress response protein, but its exact molecular functions have not been established. Studies were conducted to see whether myocilin can act as a general molecular chaperone. METHODS: Myocilin was isolated and purified from porcine trabecular meshwork (TM) cell culture media. Its ability to protect citrate synthase, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and the restriction endonuclease DrdI from thermal inactivation was evaluated. Light scattering was used to evaluate thermally induced aggregation of citrate synthase. Myocilin induction was assessed after exposure of TM cells to several types of stress treatments. RESULTS: Levels of extracellular myocilin expressed by TM cells were increased in response to mechanical stretch, heat shock, TNFα, or IL-1α. Myocilin protected citrate synthase activity against thermal inactivation for 5 minutes at 55°C in a concentration-dependent manner, with nearly full protection of 1.5 µM citrate synthase in the presence of 650 nM myocilin. Myocilin significantly reduced thermal aggregation of citrate synthase to levels 36% to 44% of control levels. Myocilin also protected GAPDH from thermal inactivation for 10 minutes at 45°C. Myocilin at 18 nM was more effective than 1 µM bovine serum albumin at protecting DrdI from thermal inactivation. CONCLUSIONS: Myocilin is induced in response to several cellular stresses and displays general molecular chaperone activity by protecting DrdI, citrate synthase, and GAPDH from thermal inactivation. Myocilin also suppresses the thermal aggregation of citrate synthase. One function of myocilin may be to serve as a molecular chaperone.


Assuntos
Proteínas do Citoesqueleto/fisiologia , Proteínas do Olho/fisiologia , Glicoproteínas/fisiologia , Chaperonas Moleculares/fisiologia , Malha Trabecular/metabolismo , Animais , Western Blotting , Células Cultivadas , Citrato (si)-Sintase/metabolismo , Desoxirribonucleases de Sítio Específico do Tipo II/metabolismo , Eletroforese em Gel de Poliacrilamida , Inibidores Enzimáticos , Gliceraldeído-3-Fosfato Desidrogenase (NADP+)(Fosforiladora)/metabolismo , Temperatura Alta , Estresse Mecânico , Estresse Fisiológico , Suínos
10.
Bioorg Med Chem Lett ; 20(9): 2933-7, 2010 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-20356736

RESUMO

The synthesis and follow-up SAR studies of our development candidate 1 by incorporating 2-aryl-4-oxazolylmethoxy and 2-aryl-4-thiazolylmethoxy moieties into the oxybenzylglycine framework of the PPARalpha/gamma dual agonist muraglitazar is described. SAR studies indicate that different substituents on the aryloxazole/thiazole moieties as well as the choice of carbamate substituent on the glycine moiety can significantly modulate the selectivity of PPARalpha versus PPARgamma. Potent, highly selective PPARalpha activators 2a and 2l, as well as PPARalpha activators with significant PPARgamma activity, such as 2s, were identified. The in vivo pharmacology of these compounds in preclinical animal models as well as their ADME profiles are discussed.


Assuntos
Anti-Inflamatórios/síntese química , Glicina/análogos & derivados , PPAR alfa/agonistas , PPAR gama/agonistas , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacocinética , Sítios de Ligação , Cricetinae , Cristalografia por Raios X , Glicina/síntese química , Glicina/farmacocinética , Humanos , Masculino , PPAR alfa/metabolismo , PPAR gama/metabolismo , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
11.
J Med Chem ; 53(7): 2854-64, 2010 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-20218621

RESUMO

An 1,3-oxybenzylglycine based compound 2 (BMS-687453) was discovered to be a potent and selective peroxisome proliferator activated receptor (PPAR) alpha agonist, with an EC(50) of 10 nM for human PPARalpha and approximately 410-fold selectivity vs human PPARgamma in PPAR-GAL4 transactivation assays. Similar potencies and selectivity were also observed in the full length receptor co-transfection assays. Compound 2 has negligible cross-reactivity against a panel of human nuclear hormone receptors including PPARdelta. Compound 2 demonstrated an excellent pharmacological and safety profile in preclinical studies and thus was chosen as a development candidate for the treatment of atherosclerosis and dyslipidemia. The X-ray cocrystal structures of the early lead compound 12 and compound 2 in complex with PPARalpha ligand binding domain (LBD) were determined. The role of the crystal structure of compound 12 with PPARalpha in the development of the SAR that ultimately resulted in the discovery of compound 2 is discussed.


Assuntos
Descoberta de Drogas , Glicina/análogos & derivados , Oxazóis/química , Oxazóis/farmacologia , PPAR alfa/agonistas , Animais , Linhagem Celular , Cricetinae , Cristalografia por Raios X , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Glicina/síntese química , Glicina/química , Glicina/farmacologia , Glicina/toxicidade , Humanos , Masculino , Camundongos , Modelos Moleculares , Oxazóis/síntese química , Oxazóis/toxicidade , PPAR alfa/química , PPAR alfa/genética , Estrutura Terciária de Proteína , Especificidade por Substrato , Ativação Transcricional/efeitos dos fármacos
12.
Bioorg Med Chem Lett ; 19(5): 1451-6, 2009 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-19201606

RESUMO

The design, synthesis and structure-activity relationships of a novel series of N-phenyl-substituted pyrrole, 1,2-pyrazole and 1,2,3-triazole acid analogs as PPAR ligands are outlined. The triazole acid analogs 3f and 4f were identified as potent dual PPARalpha/gamma agonists both in binding and functional assays in vitro. The 3-oxybenzyl triazole acetic acid analog 3f showed excellent glucose and triglyceride lowering in diabetic db/db mice.


Assuntos
Azóis/síntese química , Desenho de Drogas , PPAR alfa/agonistas , PPAR gama/agonistas , Animais , Azóis/farmacologia , Linhagem Celular/enzimologia , Cristalografia por Raios X , Feminino , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Transgênicos , PPAR alfa/metabolismo , PPAR gama/metabolismo , Relação Estrutura-Atividade
13.
Ann Vasc Surg ; 23(3): 345-9, 2009 May-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18809282

RESUMO

Mycotic femoral pseudoaneurysms, particularly in the drug-abusing population, pose a difficult problem to the vascular surgeon. Management ranges from ligation with debridement to extra-anatomical bypass. This study reviewed the management of mycotic femoral pseudoaneurysms presenting in intravenous drug abusers to an inner city tertiary referral center. Between 2001 and 2006, 11 cases presenting in nine patients were treated. The mean age was 30.7 years with a male-to-female ratio of 1:2. Eight patients had a positive viral status for the human immunodeficiency virus and/or hepatitis C. Two patients re-presented with a contralateral pseudoaneurysm. A combination of groin pain and swelling was the most common presentation. Two patients presented with significant hemorrhage. The diagnosis was confirmed by ultrasound in the majority of cases. Nine cases were managed with arterial ligation and debridement of the necrotic tissue. The two remaining cases were managed with ultrasound-guided thrombin injection and arterial puncture closure. On follow-up, one patient required a below-knee amputation following reinjection into the postoperative wound site. One further patient underwent a fifth metatarsal amputation due to ischemia. Ligation and debridement are well tolerated in the majority of drug-abusing patients diagnosed with mycotic femoral pseudoaneurysms.


Assuntos
Falso Aneurisma/cirurgia , Aneurisma Infectado/cirurgia , Usuários de Drogas , Artéria Femoral/cirurgia , Abuso de Substâncias por Via Intravenosa/complicações , Procedimentos Cirúrgicos Vasculares , Adulto , Amputação , Falso Aneurisma/diagnóstico por imagem , Falso Aneurisma/etiologia , Falso Aneurisma/microbiologia , Aneurisma Infectado/diagnóstico por imagem , Aneurisma Infectado/etiologia , Aneurisma Infectado/microbiologia , Desbridamento , Feminino , Artéria Femoral/diagnóstico por imagem , Artéria Femoral/microbiologia , Humanos , Injeções , Irlanda , Ligadura , Masculino , Reoperação , Estudos Retrospectivos , Trombina/administração & dosagem , Fatores de Tempo , Resultado do Tratamento , Ultrassonografia de Intervenção , Saúde da População Urbana , Procedimentos Cirúrgicos Vasculares/efeitos adversos
14.
J Pharmacol Exp Ther ; 327(3): 716-26, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18799592

RESUMO

The first generation peroxisome proliferator-activated receptor (PPAR) alpha agonist gemfibrozil reduces the risk of major cardiovascular events; therefore, more potent PPARalpha agonists for the treatment of cardiovascular diseases have been actively sought. We describe two novel, potent oxybenzylglycine PPARalpha-selective agonists, BMS-687453 [N-[[3-[[2-(4-chlorophenyl)-5-methyl-4-oxazolyl]methoxy]phenyl]methyl]-N-(methoxycarbonyl)-glycine] and BMS-711939 N-[[5-[[2-(4-chlorophenyl)-5-methyl-4-oxazolyl]methoxy]-2-fluorophenyl]methyl]-N-(methoxycarbonyl)-glycine], that robustly increase apolipoprotein (Apo) A1 and high-density lipoprotein cholesterol in human ApoA1 transgenic mice and lower low-density lipoprotein-cholesterol and triglycerides in fat-fed hamsters. These compounds have much lower potency against mouse PPARalpha than human PPARalpha; therefore, they were tested in PPARalpha-humanized mice that do not express murine PPARalpha but express human PPARalpha selectively in the liver. We developed hepatic gene induction as a novel biomarker for efficacy and demonstrate hepatic gene induction at very low doses of these compounds. BMS-711939 induces fecal cholesterol excretion, which is further increased upon cotreatment with a liver X receptor (LXR) agonist. It is surprising that this synergistic increase upon coadministration is also observed in mice that express PPARalpha in the liver only. BMS-711939 also prevented the LXR agonist-induced elevation of serum triglycerides. Such PPARalpha agonists could be attractive candidates to explore for the treatment of cardiovascular diseases, especially in combination with a suitable LXR agonist.


Assuntos
Colesterol/metabolismo , Proteínas de Ligação a DNA/agonistas , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , PPAR alfa/agonistas , Receptores Citoplasmáticos e Nucleares/agonistas , Triglicerídeos/sangue , Animais , Sinergismo Farmacológico , Humanos , Fígado/metabolismo , Receptores X do Fígado , Camundongos , Camundongos Transgênicos , Receptores Nucleares Órfãos , Ativação Transcricional/efeitos dos fármacos
15.
Bioorg Med Chem Lett ; 18(12): 3545-50, 2008 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-18511276

RESUMO

Several series of substituted dehydropiperidine and piperidine-4-carboxylic acid analogs have been designed and synthesized as novel, potent dual PPARalpha/gamma agonists. The SAR of these series of analogs is discussed. A rare double bond migration occurred during the basic hydrolysis of the alpha,beta-unsaturated dehydropiperidine esters 12, and the structures of the migration products were confirmed through a series of 2D NMR experiments.


Assuntos
Ácidos Carboxílicos , PPAR alfa/agonistas , PPAR gama/agonistas , Piperidinas , Ligação Competitiva/efeitos dos fármacos , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Relação Dose-Resposta a Droga , Desenho de Drogas , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Piperidinas/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade
16.
Bioorg Med Chem Lett ; 18(6): 1939-44, 2008 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-18291645

RESUMO

A novel class of azetidinone acid-derived dual PPARalpha/gamma agonists has been synthesized for the treatment of diabetes and dyslipidemia. The preferred stereochemistry in this series for binding and functional agonist activity against both PPARalpha and PPARgamma receptors was shown to be 3S,4S. Synthesis, in vitro and in vivo activities of compounds in this series are described. A high-yielding method for N-arylation of azetidinone esters is also described.


Assuntos
Azetidinas/química , Azetidinas/farmacologia , PPAR alfa/agonistas , PPAR gama/agonistas , Administração Oral , Animais , Azetidinas/síntese química , Disponibilidade Biológica , Cobre/farmacologia , Cristalografia por Raios X , Inibidores das Enzimas do Citocromo P-450 , Diabetes Mellitus Experimental/tratamento farmacológico , Dislipidemias/tratamento farmacológico , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/metabolismo , Glucose/metabolismo , Camundongos , Camundongos Mutantes , Estrutura Molecular , PPAR alfa/metabolismo , PPAR gama/metabolismo , Conformação Proteica , Estereoisomerismo , Relação Estrutura-Atividade , Triglicerídeos/sangue
17.
Anal Biochem ; 363(2): 263-74, 2007 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-17335769

RESUMO

Peroxisome proliferator-activated receptors (PPARs) and other members of the nuclear hormone receptor family are important drug targets for the treatment of metabolic diseases. PPARalpha and PPARgamma play crucial roles in lipid and glucose metabolism, respectively. Therefore, screening methods that help to rapidly identify activators of these receptors should be of considerable value. A homogeneous fluorescence polarization (FP) ligand binding assay capable of rapidly identifying ligands that bind to both PPARalpha and PPARgamma has been developed using purified PPARalpha or PPARgamma ligand binding domains and a fluorescein-labeled analog (FLA) of a potent dual PPARalpha/gamma activator. FLA activator showed good binding affinity toward both PPARalpha (K(i)=0.7microM) and PPARgamma (K(i)=0.4microM). The binding of FLA activator was rapid and reached a plateau within 10 min. The resulting FP signal was stable for at least 18h. The FP binding assay performed robustly in a 384-well format, and the average Z' value was 0.77. There was a good correlation between the binding potency (IC(50) values) and rank order of binding potency for a panel of standard PPAR ligands obtained in FP binding assay and scintillation proximity assay or gel filtration binding assays using (3)H-labeled PPARalpha (r(2)=0.99) and PPARgamma (r(2)=0.99) ligands. There was also a good correlation of IC(50) values obtained by FP binding assay and scintillation proximity assay for the clinically used PPAR activators. Thus, the FP binding assay with a single fluorescein-labeled PPARalpha/gamma dual activator offers a homogeneous nonradioactive, sensitive, robust, and less expensive high-throughput assay for detecting compounds that bind to both PPARgamma and PPARalpha. Using this FP binding assay, we have identified a large number of PPARalpha/gamma dual activators. A similar assay platform may be easily adapted to other members of the nuclear hormone receptor family.


Assuntos
Polarização de Fluorescência/métodos , Ligantes , PPAR alfa/metabolismo , PPAR gama/metabolismo , Cromatografia em Gel , Dimetil Sulfóxido/química , Humanos , Cinética , Modelos Biológicos , Estrutura Molecular , PPAR alfa/agonistas , PPAR alfa/genética , PPAR gama/agonistas , PPAR gama/genética , Ligação Proteica , Reprodutibilidade dos Testes
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