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1.
JAMA ; 322(18): 1780-1788, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31714986

RESUMO

Importance: Additional treatment options are needed for patients who do not achieve sufficient reduction in low-density lipoprotein cholesterol (LDL-C) level with available lipid-lowering therapies. Objective: To assess the efficacy of bempedoic acid vs placebo in patients at high cardiovascular risk receiving maximally tolerated lipid-lowering therapy. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled clinical trial conducted at 91 clinical sites in North America and Europe from November 2016 to September 2018, with a final date of follow-up of September 22, 2018. A total of 779 patients with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both met randomization criteria, which included LDL-C level 70 mg/dL (1.8 mmol/L) or greater while receiving maximally tolerated lipid-lowering therapy. Interventions: Patients were randomized 2:1 to treatment with bempedoic acid (180 mg) (n = 522) or placebo (n = 257) once daily for 52 weeks. Main Outcomes and Measures: The primary end point was percent change from baseline in LDL-C level at week 12. Secondary measures included changes in levels of lipids, lipoproteins, and biomarkers. Results: Among 779 randomized patients (mean age, 64.3 years; 283 women [36.3%]), 740 (95.0%) completed the trial. At baseline, mean LDL-C level was 120.4 (SD, 37.9) mg/dL. Bempedoic acid lowered LDL-C levels significantly more than placebo at week 12 (-15.1% vs 2.4%, respectively; difference, -17.4% [95% CI, -21.0% to -13.9%]; P < .001). Significant reductions with bempedoic acid vs placebo were observed at week 12 for non-high-density lipoprotein cholesterol (-10.8% vs 2.3%; difference, -13.0% [95% CI, -16.3% to -9.8%]; P < .001), total cholesterol (-9.9% vs 1.3%; difference, -11.2% [95% CI, -13.6% to -8.8%]; P < .001), apolipoprotein B (-9.3% vs 3.7%; difference, -13.0% [95% CI, -16.1% to -9.9%]; P < .001), and high-sensitivity C-reactive protein (median, -18.7% vs -9.4%; difference, -8.7% [asymptotic confidence limits, -17.2% to -0.4%]; P = .04). Common adverse events included nasopharyngitis (5.2% vs 5.1% with bempedoic acid and placebo, respectively), urinary tract infection (5.0% vs 1.9%), and hyperuricemia (4.2% vs 1.9%). Conclusions and Relevance: Among patients at high risk for cardiovascular disease receiving maximally tolerated statins, the addition of bempedoic acid compared with placebo resulted in a significant lowering of LDL-C level over 12 weeks. Further research is needed to assess the durability and clinical effect as well as long-term safety. Trial Registration: ClinicalTrials.gov Identifier: NCT02991118.


Assuntos
Anticolesterolemiantes/uso terapêutico , Aterosclerose/tratamento farmacológico , Ácidos Dicarboxílicos/uso terapêutico , Ácidos Graxos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipidemia Familiar Combinada/tratamento farmacológico , Idoso , Anticolesterolemiantes/efeitos adversos , Aterosclerose/sangue , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/sangue , Ácidos Dicarboxílicos/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada , Ácidos Graxos/efeitos adversos , Feminino , Humanos , Hiperlipidemia Familiar Combinada/sangue , Masculino , Pessoa de Meia-Idade
2.
J Clin Lipidol ; 13(4): 568-579, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31202641

RESUMO

BACKGROUND: Bempedoic acid is an oral, once-daily, first-in-class medication being developed to treat hypercholesterolemia. OBJECTIVE: The aim of the study was to assess the low-density lipoprotein cholesterol (LDL-C)-lowering efficacy of bempedoic acid added to stable high-intensity atorvastatin background therapy and multiple-dose plasma pharmacokinetics of atorvastatin alone and combined with steady-state bempedoic acid. METHODS: This was a phase 2 study in patients with hypercholesterolemia (NCT02659397). Patients received once-daily open-label atorvastatin 80 mg for 4 weeks then were randomized 2:1 at baseline to receive double-blind bempedoic acid 180 mg (n = 45) or placebo (n = 23) plus open-label atorvastatin 80 mg for 4 weeks. Efficacy was assessed 4 weeks after randomization. Atorvastatin and metabolites' steady-state levels were analyzed before first dosing with bempedoic acid and after 2 weeks of treatment. RESULTS: The 4-week stabilization phase with 80 mg atorvastatin resulted in approximately 40% lowering of LDL-C values from screening. The placebo-adjusted least squares mean lowering of LDL-C from baseline to Day 29 with bempedoic acid was 22% (P = .003). Placebo-adjusted reductions from baseline with bempedoic acid also were significant for total cholesterol (-10%; P = .014), non-high-density lipoprotein cholesterol (-13%; P = .015), apolipoprotein B (-15%; P = .004), and high-sensitivity C-reactive protein (-44%; P = .002). Point estimates of bempedoic acid effects on steady-state atorvastatin and ortho-hydroxy atorvastatin area under the curve were <30% and not clinically meaningful. CONCLUSIONS: Bempedoic acid 180 mg added to stable high-dose atorvastatin therapy effectively lowers LDL-C in patients with hypercholesterolemia without causing clinically important increases in atorvastatin exposure.

3.
Atherosclerosis ; 277: 195-203, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29910030

RESUMO

BACKGROUND AND AIMS: Patients with hyperlipidemia who are unable to tolerate optimal statin therapy are at increased cardiovascular risk due to ongoing elevations in low-density lipoprotein cholesterol (LDL-C). The objective of CLEAR Tranquility (NCT03001076) was to evaluate the efficacy and safety of bempedoic acid when added to background lipid-modifying therapy in patients with a history of statin intolerance who require additional LDL-C lowering. METHODS: This phase 3, multicenter, randomized, double-blind, placebo-controlled study enrolled patients with a history of statin intolerance and an LDL-C ≥100 mg/dL while on stable lipid-modifying therapy. After a 4-week ezetimibe 10 mg/day run-in period, patients were randomized 2:1 to treatment with bempedoic acid 180 mg or placebo once daily added to ezetimibe 10 mg/day for 12 weeks. The primary endpoint was the percent change from baseline to week 12 in LDL-C. RESULTS: The study population comprised 269 patients (181 bempedoic acid, 88 placebo). Bempedoic acid added to background lipid-modifying therapy that included ezetimibe reduced LDL-C by 28.5% more than placebo (p < 0.001; -23.5% bempedoic acid, +5.0% placebo). Significant reductions in secondary endpoints, including non-high-density lipoprotein cholesterol (-23.6%), total cholesterol (-18.0%), apolipoprotein B (-19.3%), and high-sensitivity C-reactive protein (-31.0%), were observed with bempedoic acid vs. placebo (p < 0.001). Bempedoic acid was well tolerated; rates of treatment-emergent adverse events, muscle-related adverse events, and discontinuations were similar in the bempedoic acid and placebo treatment groups. CONCLUSIONS: Bempedoic acid may provide an oral therapeutic option complementary to ezetimibe in statin intolerant patients who require additional LDL-C lowering.


Assuntos
LDL-Colesterol/sangue , Ácidos Dicarboxílicos/uso terapêutico , Ezetimiba/uso terapêutico , Ácidos Graxos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Hipercolesterolemia/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Idoso , Biomarcadores/sangue , Canadá , Ácidos Dicarboxílicos/efeitos adversos , Método Duplo-Cego , Regulação para Baixo , Quimioterapia Combinada , Europa (Continente) , Ezetimiba/efeitos adversos , Ácidos Graxos/efeitos adversos , Feminino , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/diagnóstico , Hipolipemiantes/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento , Estados Unidos
4.
Am J Cardiol ; 117(12): 1928-33, 2016 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-27138185

RESUMO

ETC-1002 is an oral, once-daily medication that inhibits adenosine triphosphate citrate lyase, an enzyme upstream of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, to reduce cholesterol biosynthesis. ETC-1002 monotherapy has demonstrated significant reduction in low-density lipoprotein cholesterol (LDL-C) compared with placebo in phase 2 studies. The objective of this study was to compare the lipid-lowering efficacy of ETC-1002 versus placebo when added to ongoing statin therapy in patients with hypercholesterolemia. This phase 2b, multicenter, double-blind trial (NCT02072161) randomized 134 hypercholesterolemic patients (LDL-C, 115 to 220 mg/dl) on stable background statin therapy to 12 weeks of add-on treatment with ETC-1002 120 mg, ETC-1002 180 mg, or placebo. The primary efficacy end point was the percent change in calculated LDL-C from baseline to week 12. For LDL-C, the least-squares mean percent change ± standard error from baseline to week 12 was significantly greater with ETC-1002 120 mg (-17 ± 4%, p = 0.0055) and ETC-1002 180 mg (-24 ± 4%, p <0.0001) than placebo (-4 ± 4%). ETC-1002 also dose dependently reduced apolipoprotein B by 15% to 17%, non-high-density lipoprotein cholesterol by 14% to 17%, total cholesterol by 13% to 15%, and LDL particle number by 17% to 21%. All these reductions in ETC-1002-treated cohorts were significantly greater than those with placebo. Rates of adverse events (AEs), muscle-related AEs, and discontinuations for AEs with ETC-1002 were similar to placebo. In conclusion, ETC-1002 120 mg or 180 mg added to stable statin therapy significantly reduced LDL-C compared to placebo and has a similar tolerability profile.


Assuntos
LDL-Colesterol/sangue , Ácidos Dicarboxílicos/uso terapêutico , Ácidos Graxos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , LDL-Colesterol/efeitos dos fármacos , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Hipercolesterolemia/sangue , Hipolipemiantes/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sinvastatina/uso terapêutico , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
5.
J Clin Lipidol ; 10(3): 556-67, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27206943

RESUMO

BACKGROUND: ETC-1002 is an oral, once-daily, first-in-class medication being developed to treat hypercholesterolemia. OBJECTIVES: To compare 2 doses of ETC-1002, alone or combined with ezetimibe 10 mg (EZE), vs EZE monotherapy for lowering low-density lipoprotein cholesterol (LDL-C). METHODS: This phase 2b, multicenter, double-blind trial-evaluated hypercholesterolemic patients (LDL-C, 130 to 220 mg/dL) with (n = 177) or without (n = 171) muscle-related intolerance to ≥2 statins; 1 at lowest approved dose. Subjects were randomized to 12-week treatment with ETC-1002 120 mg or ETC-1002 180 mg alone, EZE alone, ETC-1002 120 mg plus EZE, or ETC-1002 180 mg plus EZE. RESULTS: EZE alone lowered LDL-C by 21%, whereas ETC-1002 monotherapy with 120 mg or 180 mg reduced LDL-C by 27% (P = .0008 vs EZE) and 30% (P < .0001 vs EZE), respectively. The combination of ETC-1002, 120 mg or 180 mg plus EZE reduced LDL-C by 43% and 48%, respectively (both P < .0001 vs EZE). ETC-1002 alone or combined with EZE also reduced non-high-density lipoprotein cholesterol, total cholesterol, apolipoprotein B, LDL particle number, and high-sensitivity C-reactive protein compared with EZE alone. Across all treatment groups, statin-intolerant patients reported more muscle-related adverse events than did statin-tolerant patients. ETC-1002 was safe and well tolerated, and rates of muscle-related adverse events were similar in all treatment groups. CONCLUSIONS: In patients with and without statin intolerance, daily treatment with ETC-1002 120 mg and 180 mg alone or with EZE reduced LDL-C more than EZE alone and had a similar tolerability profile (NCT01941836).


Assuntos
LDL-Colesterol/sangue , Ezetimiba/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hipercolesterolemia/sangue , Hipercolesterolemia/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ezetimiba/uso terapêutico , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Músculos/efeitos dos fármacos , Segurança , Adulto Jovem
6.
Arterioscler Thromb Vasc Biol ; 34(3): 676-83, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24385236

RESUMO

OBJECTIVE: 8-Hydroxy-2,2,14,14-tetramethylpentadecanedioic acid (ETC-1002) is a small molecule with a unique mechanism of action shown in nonclinical studies to modulate pathways of cholesterol, fatty acid, and carbohydrate metabolism. In previous phase 2 clinical trials, once daily oral treatment with ETC-1002 significantly reduced low-density lipoprotein-cholesterol in patients with hypercholesterolemia. In this trial, the lipid-lowering efficacy of ETC-1002 was evaluated in patients with type 2 diabetes mellitus and hypercholesterolemia. Additional cardiometabolic biomarkers, including glycemic measures, were also assessed. APPROACH AND RESULTS: A single-center, double-blind, placebo-controlled trial evaluated 60 patients with type 2 diabetes mellitus and elevated low-density lipoprotein-cholesterol. Patients discontinued all diabetes mellitus and lipid-regulating drugs and were randomized to receive ETC-1002 80 mg QD for 2 weeks followed by 120 mg QD for 2 weeks or placebo for 4 weeks. ETC-1002 lowered low-density lipoprotein-cholesterol levels by 43±2.6% (least squares mean±SE), compared with a reduction of 4±2.5% by placebo at day 29 (P<0.0001; primary end point). Non-high-density lipoprotein-cholesterol and total cholesterol were also significantly lowered by ETC-1002 compared with placebo (P<0.0001). High-sensitivity C-reactive protein was reduced by 41% (median) compared with a placebo reduction of 11% (P=0.0011). No clinically meaningful safety findings were observed. CONCLUSIONS: ETC-1002 lowered low-density lipoprotein-cholesterol and other lipids and demonstrated improvement in high-sensitivity C-reactive protein in patients with type 2 diabetes mellitus and hypercholesterolemia without worsening glycemic control. ETC-1002 was well tolerated in this population. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT# 01607294.


Assuntos
Anticolesterolemiantes/uso terapêutico , LDL-Colesterol/sangue , Diabetes Mellitus Tipo 2/complicações , Ácidos Dicarboxílicos/uso terapêutico , Ácidos Graxos/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Idoso , Anticolesterolemiantes/efeitos adversos , Anti-Hipertensivos/uso terapêutico , Glicemia/análise , Pressão Sanguínea , Proteína C-Reativa/análise , HDL-Colesterol/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Ácidos Dicarboxílicos/efeitos adversos , Método Duplo-Cego , Jejum/sangue , Ácidos Graxos/efeitos adversos , Feminino , Humanos , Hipercolesterolemia/complicações , Hipertensão/sangue , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Triglicerídeos/sangue
7.
J Lipid Res ; 54(8): 2095-108, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23709692

RESUMO

ETC-1002 is an investigational drug currently in Phase 2 development for treatment of dyslipidemia and other cardiometabolic risk factors. In dyslipidemic subjects, ETC-1002 not only reduces plasma LDL cholesterol but also significantly attenuates levels of hsCRP, a clinical biomarker of inflammation. Anti-inflammatory properties of ETC-1002 were further investigated in primary human monocyte-derived macrophages and in in vivo models of inflammation. In cells treated with ETC-1002, increased levels of AMP-activated protein kinase (AMPK) phosphorylation coincided with reduced activity of MAP kinases and decreased production of proinflammatory cytokines and chemokines. AMPK phosphorylation and inhibitory effects of ETC-1002 on soluble mediators of inflammation were significantly abrogated by siRNA-mediated silencing of macrophage liver kinase B1 (LKB1), indicating that ETC-1002 activates AMPK and exerts its anti-inflammatory effects via an LKB1-dependent mechanism. In vivo, ETC-1002 suppressed thioglycollate-induced homing of leukocytes into mouse peritoneal cavity. Similarly, in a mouse model of diet-induced obesity, ETC-1002 restored adipose AMPK activity, reduced JNK phosphorylation, and diminished expression of macrophage-specific marker 4F/80. These data were consistent with decreased epididymal fat-pad mass and interleukin (IL)-6 release by inflamed adipose tissue. Thus, ETC-1002 may provide further clinical benefits for patients with cardiometabolic risk factors by reducing systemic inflammation linked to insulin resistance and vascular complications of metabolic syndrome.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Tecido Adiposo/efeitos dos fármacos , Anti-Inflamatórios não Esteroides/farmacologia , Ácidos Dicarboxílicos/farmacologia , Ácidos Graxos/farmacologia , Leucócitos/efeitos dos fármacos , Macrófagos/enzimologia , Proteínas Serina-Treonina Quinases/metabolismo , Tecido Adiposo/citologia , Tecido Adiposo/imunologia , Animais , Relação Dose-Resposta a Droga , Humanos , Inflamação , Leucócitos/citologia , Leucócitos/imunologia , Macrófagos/efeitos dos fármacos , Masculino , Fosforilação , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
8.
J Lipid Res ; 54(1): 134-51, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23118444

RESUMO

ETC-1002 (8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid) is a novel investigational drug being developed for the treatment of dyslipidemia and other cardio-metabolic risk factors. The hypolipidemic, anti-atherosclerotic, anti-obesity, and glucose-lowering properties of ETC-1002, characterized in preclinical disease models, are believed to be due to dual inhibition of sterol and fatty acid synthesis and enhanced mitochondrial long-chain fatty acid ß-oxidation. However, the molecular mechanism(s) mediating these activities remained undefined. Studies described here show that ETC-1002 free acid activates AMP-activated protein kinase in a Ca(2+)/calmodulin-dependent kinase ß-independent and liver kinase ß 1-dependent manner, without detectable changes in adenylate energy charge. Furthermore, ETC-1002 is shown to rapidly form a CoA thioester in liver, which directly inhibits ATP-citrate lyase. These distinct molecular mechanisms are complementary in their beneficial effects on lipid and carbohydrate metabolism in vitro and in vivo. Consistent with these mechanisms, ETC-1002 treatment reduced circulating proatherogenic lipoproteins, hepatic lipids, and body weight in a hamster model of hyperlipidemia, and it reduced body weight and improved glycemic control in a mouse model of diet-induced obesity. ETC-1002 offers promise as a novel therapeutic approach to improve multiple risk factors associated with metabolic syndrome and benefit patients with cardiovascular disease.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , ATP Citrato (pro-S)-Liase/metabolismo , Metabolismo dos Carboidratos/efeitos dos fármacos , Ácidos Dicarboxílicos/farmacologia , Inibidores Enzimáticos/farmacologia , Ácidos Graxos/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Terapia de Alvo Molecular/métodos , ATP Citrato (pro-S)-Liase/antagonistas & inibidores , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , Cálcio/metabolismo , Cricetinae , Ácidos Dicarboxílicos/química , Ácidos Dicarboxílicos/uso terapêutico , Dieta/efeitos adversos , Dislipidemias/sangue , Dislipidemias/tratamento farmacológico , Dislipidemias/metabolismo , Metabolismo Energético/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Ácidos Graxos/biossíntese , Ácidos Graxos/química , Ácidos Graxos/uso terapêutico , Feminino , Glucagon/metabolismo , Glucose/biossíntese , Células Hep G2 , Humanos , Fígado/citologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Masculino , Camundongos , Obesidade/sangue , Obesidade/tratamento farmacológico , Obesidade/etiologia , Obesidade/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Esteróis/biossíntese
9.
J Lipid Res ; 53(12): 2490-514, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22798688

RESUMO

The adenosine monophosphate-activated protein kinase (AMPK) is a metabolic sensor of energy metabolism at the cellular as well as whole-body level. It is activated by low energy status that triggers a switch from ATP-consuming anabolic pathways to ATP-producing catabolic pathways. AMPK is involved in a wide range of biological activities that normalizes lipid, glucose, and energy imbalances. These pathways are dysregulated in patients with metabolic syndrome (MetS), which represents a clustering of major cardiovascular risk factors including diabetes, lipid abnormalities, and energy imbalances. Clearly, there is an unmet medical need to find a molecule to treat alarming number of patients with MetS. AMPK, with multifaceted activities in various tissues, has emerged as an attractive drug target to manage lipid and glucose abnormalities and maintain energy homeostasis. A number of AMPK activators have been tested in preclinical models, but many of them have yet to reach to the clinic. This review focuses on the structure-function and role of AMPK in lipid, carbohydrate, and energy metabolism. The mode of action of AMPK activators, mechanism of anti-inflammatory activities, and preclinical and clinical findings as well as future prospects of AMPK as a drug target in treating cardio-metabolic disease are discussed.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Metabolismo dos Carboidratos , Doenças Cardiovasculares/tratamento farmacológico , Ativadores de Enzimas/farmacologia , Ativadores de Enzimas/uso terapêutico , Metabolismo dos Lipídeos , Proteínas Quinases Ativadas por AMP/química , Animais , Doenças Cardiovasculares/enzimologia , Doenças Cardiovasculares/metabolismo , Ativadores de Enzimas/administração & dosagem , Humanos
10.
G3 (Bethesda) ; 2(4): 499-504, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22540041

RESUMO

The site 1 protease, encoded by Mbtps1, mediates the initial cleavage of site 2 protease substrates, including sterol regulatory element binding proteins and CREB/ATF transcription factors. We demonstrate that a hypomorphic mutation of Mbtps1 called woodrat (wrt) caused hypocholesterolemia, as well as progressive hypopigmentation of the coat, that appears to be mechanistically unrelated. Hypopigmentation was rescued by transgenic expression of wild-type Mbtps1, and reciprocal grafting studies showed that normal pigmentation depended upon both cell-intrinsic or paracrine factors, as well as factors that act systemically, both of which are lacking in wrt homozygotes. Mbtps1 exhibited a maternal-zygotic effect characterized by fully penetrant embryonic lethality of maternal-zygotic wrt mutant offspring and partial embryonic lethality (~40%) of zygotic wrt mutant offspring. Mbtps1 is one of two maternal-zygotic effect genes identified in mammals to date. It functions nonredundantly in pigmentation and embryogenesis.

11.
Bioorg Med Chem Lett ; 21(9): 2725-31, 2011 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-21183342

RESUMO

The design of drugs with selective tissue distribution can be an effective strategy for enhancing efficacy and safety, but understanding the translation of preclinical tissue distribution data to the clinic remains an important challenge. As part of a discovery program to identify next generation liver selective HMG-CoA reductase inhibitors we report the identification of (3R,5R)-7-(4-((3-fluorobenzyl)carbamoyl)-5-cyclopropyl-2-(4-fluorophenyl)-1H-imidazol-1-yl)-3,5-dihydroxyheptanoic acid (26) as a candidate for treating hypercholesterlemia. Clinical evaluation of 26 (PF-03491165), as well as the previously reported 2 (PF-03052334), provided an opportunity for a case study comparison of the preclinical and clinical pharmacokinetics as well as pharmacodynamics of tissue targeted HMG-CoA reductase inhibitors.


Assuntos
Descoberta de Drogas , Ácidos Heptanoicos/síntese química , Inibidores de Hidroximetilglutaril-CoA Redutases/síntese química , Hipercolesterolemia/tratamento farmacológico , Imidazóis/síntese química , Fígado/efeitos dos fármacos , Animais , Células Cultivadas , Cães , Relação Dose-Resposta a Droga , Hepatócitos/efeitos dos fármacos , Ácidos Heptanoicos/química , Ácidos Heptanoicos/farmacocinética , Ácidos Heptanoicos/farmacologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Imidazóis/química , Imidazóis/farmacocinética , Imidazóis/farmacologia , Concentração Inibidora 50 , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Pirazóis/farmacocinética , Pirazóis/farmacologia , Ratos , Distribuição Tecidual
12.
Atherosclerosis ; 212(1): 48-54, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20630529

RESUMO

OBJECTIVE: Animal models of atherosclerosis are essential to elucidate disease mechanisms and develop new therapies. Each model features advantages and disadvantages in exemplifying the pathophysiology of human atherosclerosis. Diet-induced development of atherosclerosis in Octodon degus (degu) was examined to demonstrate the potential of the degu as a model of human atherosclerosis. METHODS: Degus were fed for 16 weeks with either normal chow or chow containing 0.25% cholesterol and 6% palm oil to induce atherosclerosis. The lipid compositions of plasma lipoproteins and aortas were determined. Locations of aortic lesions were mapped by imaging of fluorescently stained aortic lesions. Lesion morphology in the brachiocephalic artery was detected by histological staining. RESULTS: Total plasma cholesterol in chow-fed degus was distributed approximately 60% in HDL, 30% in LDL and less than 10% in VLDL. Cholesterol-fed degus exhibited 4- to 5-fold increases in total plasma cholesterol, principally in the VLDL and LDL fractions. Cholesteryl ester transfer protein activity of similar magnitude to that in human plasma was detected in chow-fed degu plasma. Cholesterol-fed degus developed cholesteryl ester-rich atherosclerotic lesions throughout the aorta. Histological examination of lesions in the brachiocephalic artery showed well-formed, foam cell-rich lesions populated with inflammatory cells. It is also noteworthy that all the degus in this study exhibited hyperglycemia. CONCLUSION: These results demonstrate that degus have a human-like lipoprotein metabolism and develop extensive atherosclerosis with cholesterol feeding in the presence of hyperglycemia. These features, combined with the manageable size and handling characteristics, point to the potential of the degu as a useful model for atherosclerosis research.


Assuntos
Doenças da Aorta , Aterosclerose , Modelos Animais de Doenças , Octodon , Animais , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/sangue , Doenças da Aorta/etiologia , Doenças da Aorta/patologia , Aterosclerose/sangue , Aterosclerose/etiologia , Aterosclerose/patologia , Biomarcadores/sangue , Glicemia/metabolismo , Tronco Braquiocefálico/metabolismo , Tronco Braquiocefálico/patologia , Proteínas de Transferência de Ésteres de Colesterol/sangue , Colesterol na Dieta/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , VLDL-Colesterol/sangue , Feminino , Humanos , Hiperglicemia/sangue , Hiperglicemia/etiologia , Masculino , Óleo de Palmeira , Óleos Vegetais , Fatores de Tempo
13.
J Med Chem ; 51(1): 31-45, 2008 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-18072721

RESUMO

In light of accumulating evidence that aggressive LDL-lowering therapy may offer increased protection against coronary heart disease, we undertook the design and synthesis of a novel series of HMG-CoA reductase inhibitors based upon a substituted pyrazole template. Optimizing this series using both structure-based design and molecular property considerations afforded a class of highly efficacious and hepatoselective inhibitors resulting in the identification of (3 R,5 R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2 H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic (PF-3052334) as a candidate for the treatment of hypercholesterolemia.


Assuntos
Ácidos Heptanoicos/síntese química , Inibidores de Hidroximetilglutaril-CoA Redutases/síntese química , Hipercolesterolemia/tratamento farmacológico , Fígado/efeitos dos fármacos , Pirazóis/síntese química , Animais , LDL-Colesterol/biossíntese , LDL-Colesterol/sangue , Cricetinae , Cobaias , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Ácidos Heptanoicos/química , Ácidos Heptanoicos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Técnicas In Vitro , Fígado/metabolismo , Masculino , Mesocricetus , Células Musculares/efeitos dos fármacos , Células Musculares/metabolismo , Pirazóis/química , Pirazóis/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-Atividade
14.
Bioorg Med Chem Lett ; 18(3): 1151-6, 2008 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-18155906

RESUMO

4-Sulfamoyl pyrroles were designed as novel hepatoselective HMG-CoA reductase inhibitors (statins) to reduce myalgia, a statin-induced adverse effect. The compounds were prepared via a [3+2] cycloaddition of a Münchnone with a sulfonamide-substituted alkyne. We identified compounds with greater selectivity for hepatocytes compared to L6-myocytes than rosuvastatin and atorvastatin. There was an inverse correlation of myocyte potencies and ClogP values. A number of analogs were effective at reducing cholesterol in acute and chronic in vivo models but they lacked sufficient chronic in vivo activity to warrant further development.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/síntese química , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Células Musculares/efeitos dos fármacos , Pirróis/síntese química , Pirróis/farmacologia , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Animais , Atorvastatina , Técnicas de Química Combinatória , Modelos Animais de Doenças , Fluorbenzenos/farmacologia , Hepatócitos/efeitos dos fármacos , Ácidos Heptanoicos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Camundongos , Estrutura Molecular , Pirimidinas/farmacologia , Pirróis/química , Rosuvastatina Cálcica
15.
Bioorg Med Chem Lett ; 17(20): 5567-72, 2007 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-17764936

RESUMO

An extraordinarily potent and hepatoselective class of HMG-CoA reductase inhibitors containing a pyrazole core was recently reported; however, its development was hampered by a long and difficult synthetic route. We attempted to circumvent this obstacle by preparing closely related analogs wherein the key dihydroxyheptanoic acid sidechain was tethered to the pyrazole core via an oxygen linker ('oxypyrazoles'). This minor change reduced the total number of synthetic steps from 14 to 7. Although the resulting analogs maintained much of the in vitro and cell activity of the pyrazoles, inferior in vivo activity precluded further development. Caco-2 cell permeability data suggest that enhanced cellular efflux of the oxypyrazoles relative to the pyrazoles may be responsible for the poor in vivo activity.


Assuntos
Desenho de Drogas , Hidroximetilglutaril-CoA Redutases/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Animais , Linhagem Celular , Cricetinae , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/síntese química , Fígado/efeitos dos fármacos , Fígado/enzimologia , Estrutura Molecular , Células Musculares/efeitos dos fármacos , Células Musculares/enzimologia , Pirazóis/síntese química , Ratos , Relação Estrutura-Atividade
16.
Bioorg Med Chem Lett ; 17(16): 4531-7, 2007 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-17574411

RESUMO

Using structure-based design, a novel series of conformationally restricted, pyrrole-based inhibitors of HMG-CoA reductase were discovered. Leading analogs demonstrated potent inhibition of cholesterol synthesis in both in vitro and in vivo models and may be useful for the treatment of hypercholesterolemia and related lipid disorders.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/síntese química , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Pirróis/química , Pirróis/farmacologia , Animais , Colesterol/biossíntese , Desenho de Drogas , Hiperlipidemias/tratamento farmacológico , Camundongos , Biologia Molecular , Estrutura Molecular , Relação Estrutura-Atividade
17.
Bioorg Med Chem Lett ; 17(16): 4538-44, 2007 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-17574412

RESUMO

This manuscript describes the design and synthesis of a series of pyrrole-based inhibitors of HMG-CoA reductase for the treatment of hypercholesterolemia. Analogs were optimized using structure-based design and physical property considerations resulting in the identification of 44, a hepatoselective HMG-CoA reductase inhibitor with excellent acute and chronic efficacy in a pre-clinical animal models.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/química , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Pirróis/química , Pirróis/farmacologia , Animais , Cricetinae , Relação Dose-Resposta a Droga , Desenho de Drogas , Fluorbenzenos , Hiperlipidemias/tratamento farmacológico , Fígado/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Pirimidinas , Rosuvastatina Cálcica , Relação Estrutura-Atividade , Sulfonamidas
18.
Bioorg Med Chem ; 15(16): 5576-89, 2007 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-17560788

RESUMO

In an effort to identify hepatoselective inhibitors of HMG-CoA reductase, two series of pyrroles were synthesized and evaluated. Efforts were made to modify (3R,5R)-7-[3-(4-fluorophenyl)-1-isopropyl-4-phenyl-5-phenylcarbamoyl-1H-pyrrol-2-yl]-3,5-dihydroxy-heptanoic acid sodium salt 30 in order to reduce its lipophilicity and therefore increase hepatoselectivity. Two strategies that were explored were replacement of the lipophilic 3-phenyl substituent with either a polar function (pyridyl series) or with lower alkyl substituents (lower alkyl series) and attachment of additional polar moieties at the 2-position of the pyrrole ring. One compound was identified to be both highly hepatoselective and active in vivo. We report the discovery, synthesis, and optimization of substituted pyrrole-based hepatoselective ligands as potent inhibitors of HMG-CoA reductase for reducing low density lipoprotein cholesterol (LDL-c) in the treatment of hypercholesterolemia.


Assuntos
Hidroximetilglutaril-CoA Redutases/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/síntese química , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Pirróis/química , Pirróis/farmacologia , Animais , Colesterol/biossíntese , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Ligantes , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Estrutura Molecular , Pirróis/síntese química , Ratos , Ratos Sprague-Dawley
19.
Atherosclerosis ; 189(2): 264-72, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16458317

RESUMO

Plasma sphingomyelin (SM) has been suggested as a risk factor for coronary heart disease independent of cholesterol levels. A decrease of SM in lipoproteins is known to improve the activities of lecithin:cholesterol acyltransferase (LCAT) and lipoprotein lipase (LPL) in vitro. Inhibition of SM biosynthesis may reduce lipoprotein SM content and thus improve cholesterol distribution in lipoproteins by enhancing reverse cholesterol transport and clearance of triglyceride-rich lipoproteins. To examine this hypothesis, ApoE KO mice were fed a western diet and treated for 4 weeks with various concentrations of myriocin, a specific inhibitor of serine palmitoyltransferase. Myriocin treatment lowered plasma cholesterol and TG levels in a dose-dependent manner. In addition, myriocin treatment reduced cholesterol contents in VLDL and LDL and elevated HDL-cholesterol. Observed lipid-lowering effects of myriocin were associated with suppression of HMG CoA reductase and fatty acid synthase via reduced levels of SREBP-1 RNA and protein. Induction of apoAI and lecithin:cholesterol acytransferase (LCAT) in the liver by myriocin was associated with an increased HDL. Lesion area and macrophage area were also diminished in the cuffed femoral artery of ApoE KO mice. In conclusion, inhibition of sphingolipid biosynthesis can be a novel therapeutic target for dyslipidemia and atherosclerosis.


Assuntos
Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Ácidos Graxos Monoinsaturados/uso terapêutico , Esfingomielinas/antagonistas & inibidores , Esfingomielinas/biossíntese , Animais , Apolipoproteínas E/deficiência , Western Blotting , HDL-Colesterol/sangue , LDL-Colesterol/sangue , VLDL-Colesterol/sangue , Modelos Animais de Doenças , Regulação da Expressão Gênica , Imunossupressores/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase , RNA/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
20.
Circulation ; 110(22): 3465-71, 2004 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-15545514

RESUMO

BACKGROUND: In clinical studies, sphingomyelin (SM) plasma levels correlated with the occurrence of coronary heart disease independently of plasma cholesterol levels. We hypothesized that inhibition of SM synthesis would have antiatherogenic effects. To test this hypothesis, apolipoprotein E (apoE)-knockout (KO) mice were treated with myriocin, a potent inhibitor of serine palmitoyltransferase, the rate-limiting enzyme in SM biosynthesis. METHODS AND RESULTS: Diet-admix treatment of apoE-KO mice with myriocin in Western diet for 12 weeks lowered SM and sphinganine plasma levels. Decreases in sphinganine and SM concentrations were also observed in the liver and aorta of myriocin-treated animals compared with controls. Inhibition of de novo sphingolipid biosynthesis reduced total cholesterol and triglyceride plasma levels. Cholesterol distribution in lipoproteins demonstrated a decrease in beta-VLDL and LDL cholesterol and an increase in HDL cholesterol. Oil red O staining of total aortas demonstrated reduction of atherosclerotic lesion coverage in the myriocin-treated group. Atherosclerotic plaque area was also reduced in the aortic root and brachiocephalic artery. CONCLUSIONS: Inhibition of de novo SM biosynthesis in apoE-KO mice lowers plasma cholesterol and triglyceride levels, raises HDL cholesterol, and prevents development of atherosclerotic lesions.


Assuntos
Aciltransferases/antagonistas & inibidores , Apolipoproteínas E/deficiência , Arteriosclerose/prevenção & controle , Ácidos Graxos Monoinsaturados/uso terapêutico , Esfingomielinas/biossíntese , Esfingosina/análogos & derivados , Aciltransferases/genética , Aciltransferases/metabolismo , Animais , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/sangue , Doenças da Aorta/enzimologia , Doenças da Aorta/etiologia , Doenças da Aorta/patologia , Doenças da Aorta/prevenção & controle , Apolipoproteínas E/genética , Arteriosclerose/sangue , Arteriosclerose/enzimologia , Arteriosclerose/etiologia , Arteriosclerose/patologia , Colesterol/sangue , Cromatografia Líquida de Alta Pressão , Dieta Aterogênica , Avaliação Pré-Clínica de Medicamentos , Indução Enzimática/efeitos dos fármacos , Ácidos Graxos Monoinsaturados/farmacologia , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/complicações , Hiperlipoproteinemia Tipo II/enzimologia , Hiperlipoproteinemia Tipo II/genética , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfolipídeos/sangue , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Risco , Serina C-Palmitoiltransferase , Esfingomielinas/sangue , Esfingosina/sangue , Linfócitos T/patologia , Triglicerídeos/sangue
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