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1.
Drug Metab Dispos ; 47(3): 227-233, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30567880

RESUMO

Anacetrapib is an inhibitor of cholesteryl ester transfer protein (CETP), associated with reduction in LDL cholesterol and increase in HDL cholesterol in hypercholesterolemic patients. Anacetrapib was not taken forward into filing/registration as a new drug for coronary artery diease, despite the observation of a ∼9% reduction in cardiovascular risk in a large phase III cardiovascular outcomes trial (REVEAL). Anacetrapib displayed no adverse effects throughout extensive preclinical safety evaluation, and no major safety signals were observed in clinical trials studying anacetrapib, including REVEAL. However, anacetrapib demonstrated a long terminal half-life in all species, thought to be due, in part, to distribution into adipose tissue. We sought to understand the dependence of anacetrapib's long half-life on adipose tissue and to explore potential mechanisms that might contribute to the phenomenon. In mice, anacetrapib localized primarily to the lipid droplet of adipocytes in white adipose tissue; in vitro, anacetrapib entry into cultured human adipocytes depended on the presence of a mature adipocyte and lipid droplet but did not require active transport. In vivo, the entry of anacetrapib into adipose tissue did not require lipase activity, as the distribution of anacetrapib into adipose was-not affected by systemic lipase inhibition using poloaxamer-407, a systemic lipase inhibitor. The data from these studies support the notion that the entry of anacetrapib into adipose tissue/lipid droplets does not require active transport, nor does it require mobilization or entry of fat into adipose via lipolysis.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Gotículas Lipídicas/metabolismo , Oxazolidinonas/farmacologia , Adipócitos/citologia , Tecido Adiposo/citologia , Animais , Linhagem Celular , HDL-Colesterol/sangue , HDL-Colesterol/metabolismo , LDL-Colesterol/sangue , LDL-Colesterol/metabolismo , Meia-Vida , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases , Hipercolesterolemia/sangue , Hipercolesterolemia/tratamento farmacológico , Lipase/antagonistas & inibidores , Lipase/metabolismo , Lipólise/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxazolidinonas/administração & dosagem , Oxazolidinonas/uso terapêutico , Poloxâmero/farmacologia , Distribuição Tecidual/efeitos dos fármacos
2.
Metabolism ; 61(4): 470-81, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22001333

RESUMO

The objective was to assess whether pharmacological activation of lecithin cholesterol acyltransferase (LCAT) could exert beneficial effects on lipoprotein metabolism. A putative small molecule activator (compound A) was used as a tool compound in in vitro and in vivo studies. Compound A increased LCAT activity in vitro in plasma from mouse, hamster, rhesus monkey, and human. To assess the acute pharmacodynamic effects of compound A, C57Bl/6 mice and hamsters received a single dose (20 mg/kg) of compound A. Both species displayed a significant increase in high-density lipoprotein cholesterol (HDLc) and a significant decrease in non-HDLc and triglycerides acutely after dosing; these changes tracked with ex vivo plasma LCAT activity. To examine compound A's chronic effect on lipoprotein metabolism, hamsters received a daily dosing of vehicle or of 20 or 60 mg/kg of compound A for 2 weeks. At study termination, compound treatment resulted in a significant increase in HDLc, HDL particle size, plasma apolipoprotein A-I level, and plasma cholesteryl ester (CE) to free cholesterol ratio, and a significant reduction in very low-density lipoprotein cholesterol. The increase in plasma CE mirrored the increase in HDL CE. Triglycerides trended toward a dose-dependent decrease in very low-density lipoprotein and HDL, with multiple triglyceride species reaching statistical significance. Gallbladder bile acids content displayed a significant and more than 2-fold increase with the 60 mg/kg treatment. We characterized pharmacological activation of LCAT by a small molecule extensively for the first time, and our findings support the potential of this approach in treating dyslipidemia and atherosclerosis; our analyses also provide mechanistic insight on LCAT's role in lipoprotein metabolism.


Assuntos
Ativação Enzimática/fisiologia , Lipoproteínas/metabolismo , Fígado/metabolismo , Fosfatidilcolina-Esterol O-Aciltransferase/metabolismo , Tiadiazóis/farmacologia , Animais , Ácidos e Sais Biliares/sangue , Colesterol/sangue , Ésteres do Colesterol/sangue , Cricetinae , Ativação Enzimática/efeitos dos fármacos , Feminino , Lipoproteínas HDL/sangue , Fígado/enzimologia , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Mesocricetus , Camundongos , Camundongos Endogâmicos C57BL , Tiadiazóis/química , Triglicerídeos/sangue
3.
J Cardiovasc Transl Res ; 4(6): 801-10, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21822774

RESUMO

Lecithin:cholesterol acyltransferase (LCAT) is the key circulating enzyme responsible for high-density lipoprotein (HDL) cholesterol esterification, HDL maturation, and potentially reverse cholesterol transport. To further explore LCAT's mechanism of action on lipoprotein metabolism, we employed adeno-associated viral vector (AAV) serotype 8 to achieve long-term (32-week) high level expression of human LCAT in hCETP;Ldlr(+/-) mice, and characterized the lipid profiles in detail. The mice had a marked increase in HDL cholesterol, HDL particle size, and significant reduction in low-density lipoprotein (LDL) cholesterol, plasma triglycerides, and plasma apoB. Plasma LCAT activity significantly increased with humanized substrate specificity. HDL cholesteryl esters increased in a fashion that fits human LCAT specificity. HDL phosphatidylcholines trended toward decrease, with no change observed for HDL lysophosphatidylcholines. Triglycerides reduction appeared to reside in all lipoprotein particles (very low-density lipoprotein (VLDL), LDL, and HDL), with HDL triglycerides composition highly reflective of VLDL, suggesting that changes in HDL triglycerides were primarily driven by the altered triglycerides metabolism in VLDL. In summary, in this human-like model for lipoprotein metabolism, AAV8-mediated overexpression of human LCAT resulted in profound changes in plasma lipid profiles. Detailed lipid analyses in the lipoprotein particles suggest that LCAT's beneficial effect on lipid metabolism includes not only enhanced HDL cholesterol esterification but also improved metabolism of apoB-containing particles and triglycerides. Our findings thus shed new light on LCAT's mechanism of action and lend support to its therapeutic potential in treating dyslipidemia.


Assuntos
Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Dependovirus/genética , Dislipidemias/terapia , Técnicas de Transferência de Genes , Terapia Genética , Vetores Genéticos , Lipídeos/sangue , Fosfatidilcolina-Esterol O-Aciltransferase/genética , Receptores de LDL/deficiência , Animais , Proteínas de Transferência de Ésteres de Colesterol/genética , Modelos Animais de Doenças , Dislipidemias/enzimologia , Dislipidemias/genética , Humanos , Fígado/enzimologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Tamanho da Partícula , Fosfatidilcolina-Esterol O-Aciltransferase/metabolismo , Receptores de LDL/genética , Fatores de Tempo
4.
Bioorg Med Chem Lett ; 20(11): 3426-30, 2010 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-20444602

RESUMO

Niacin is an effective drug for raising HDL cholesterol. However, niacin must be taken in large doses and significant side effects are often observed, including facial flushing, loss of glucose tolerance, and liver toxicity. An anthranilic acid was identified as an agonist of the niacin receptor. In order to improve efficacy and provide structural diversity, replacements for the anthranilic acid were investigated and several compounds with improved properties were identified.


Assuntos
Niacina/metabolismo , Receptores de Droga/metabolismo , ortoaminobenzoatos/química , Disponibilidade Biológica
5.
Bioorg Med Chem Lett ; 20(11): 3372-5, 2010 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-20452209

RESUMO

A series of pyrazolyl propionyl cyclohexenamides were discovered as full agonists for the high affinity niacin receptor GPR109A. The structure-activity relationship (SAR) studies were aimed to improve activity on GPR109A, reduce Cytochrome P450 2C8 (CYP2C8) and Cytochrome P450 2C9 (CYP2C9) inhibition, reduce serum shift and improve pharmacokinetic (PK) profiles.


Assuntos
Amidas/química , Cicloexenos/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Animais , Cicloexenos/química , Cicloexenos/farmacocinética , Camundongos , Ratos , Receptores Nicotínicos , Relação Estrutura-Atividade
6.
J Med Chem ; 53(6): 2666-70, 2010 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-20184326
7.
Bioorg Med Chem Lett ; 19(16): 4768-72, 2009 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-19592242

RESUMO

Niacin is an effective drug for raising HDL cholesterol and reducing coronary risks, but patients show low compliance with treatment due to severe facial flushing upon taking the drug. A series of bicyclic pyrazole carboxylic acids were synthesized and tested for their ability to activate the niacin receptor. One analog, 23, showed improved potency and lacked flushing at doses that effectively altered the lipid profile of rats.


Assuntos
Dislipidemias/tratamento farmacológico , Hipolipemiantes/farmacologia , Niacina/farmacologia , Agonistas Nicotínicos/farmacologia , Pirazóis/farmacologia , Animais , HDL-Colesterol/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Hipolipemiantes/síntese química , Hipolipemiantes/química , Camundongos , Niacina/química , Agonistas Nicotínicos/síntese química , Agonistas Nicotínicos/química , Pirazóis/síntese química , Pirazóis/química , Ratos , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo
8.
J Med Chem ; 52(8): 2587-602, 2009 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-19309152

RESUMO

Tricyclic analogues were rationally designed as the high affinity niacin receptor G-protein-coupled receptor 109A (GPR109A) agonists by overlapping three lead structures. Various tricyclic anthranilide and cycloalkene carboxylic acid full agonists were discovered with excellent in vitro activity. Compound 2g displayed a good therapeutic index regarding free fatty acids (FFA) reduction and vasodilation effects in rats, with very weak cytochrome P450 2C8 (CYP2C8) and cytochrome P450 2C9 (CYP2C9) inhibition, and a good mouse pharmacokinetics (PK) profile.


Assuntos
Cicloparafinas/síntese química , Rubor/induzido quimicamente , Compostos Heterocíclicos com 3 Anéis/síntese química , Hipolipemiantes/síntese química , Niacina/metabolismo , Receptores Acoplados a Proteínas G/agonistas , ortoaminobenzoatos/síntese química , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Células CHO , Cricetinae , Cricetulus , Cicloparafinas/efeitos adversos , Cicloparafinas/farmacologia , Orelha/irrigação sanguínea , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Hipolipemiantes/efeitos adversos , Hipolipemiantes/farmacologia , Técnicas In Vitro , Lipólise , Masculino , Camundongos , Ensaio Radioligante , Ratos , Receptores Nicotínicos , Relação Estrutura-Atividade , Vasodilatação/efeitos dos fármacos , ortoaminobenzoatos/efeitos adversos , ortoaminobenzoatos/farmacologia
9.
Bioorg Med Chem Lett ; 18(11): 3163-7, 2008 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-18477506

RESUMO

The design, synthesis, and biological activity of a series of cycloalkene acid-based niacin receptor agonists are described. This led to the discovery that tetrahydro anthranilic acid is an excellent surrogate for anthranilic acid. Several compounds were identified that were potent against the niacin receptor, had enhanced cytochrome P450 selectivity against subtypes CYP2C8 and CYP2C9, and improved oral exposure in mice.


Assuntos
Cicloexenos/síntese química , Cicloexenos/farmacologia , Ciclopentanos/síntese química , Ciclopentanos/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Agonistas Nicotínicos/síntese química , Agonistas Nicotínicos/farmacologia , ortoaminobenzoatos/síntese química , ortoaminobenzoatos/farmacologia , Animais , Hidrocarboneto de Aril Hidroxilases/efeitos dos fármacos , Cicloexenos/química , Cicloexenos/farmacocinética , Ciclopentanos/química , Ciclopentanos/farmacocinética , Citocromo P-450 CYP2C8 , Citocromo P-450 CYP2C9 , Desenho de Fármacos , Humanos , Camundongos , Agonistas Nicotínicos/química , Antagonistas Nicotínicos/farmacologia , ortoaminobenzoatos/química , ortoaminobenzoatos/farmacocinética
10.
J Med Chem ; 50(25): 6303-6, 2007 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-17994679

RESUMO

Biaryl anthranilides are reported as potent and selective full agonists for the high affinity niacin receptor GPR109A. The SAR presented outlines approaches to reduce serum shift and both CYPCYP2C8 and CYP2C9 liabilities, while improving PK and maintaining excellent receptor activity. Compound 2i exhibited good in vivo antilipolytic efficacy while providing a significantly improved therapeutic index over vasodilation (flushing) with respect to niacin in the mouse model.


Assuntos
Receptores Acoplados a Proteínas G/agonistas , ortoaminobenzoatos/síntese química , Amidas/síntese química , Amidas/farmacocinética , Amidas/farmacologia , Animais , Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores , Ligação Competitiva , Células CHO , Cricetinae , Cricetulus , Citocromo P-450 CYP2C8 , Citocromo P-450 CYP2C9 , Humanos , Técnicas In Vitro , Camundongos , Microssomos Hepáticos/metabolismo , Ensaio Radioligante , Receptores Nicotínicos , Relação Estrutura-Atividade , ortoaminobenzoatos/farmacocinética , ortoaminobenzoatos/farmacologia
11.
Genes Dev ; 20(8): 966-76, 2006 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-16598039

RESUMO

Covalent histone post-translational modifications such as acetylation, methylation, phosphorylation, and ubiquitylation play pivotal roles in regulating many cellular processes, including transcription, response to DNA damage, and epigenetic control. Although positive-acting post-translational modifications have been studied in Saccharomyces cerevisiae, histone modifications that are associated with transcriptional repression have not been shown to occur in this yeast. Here, we provide evidence that histone sumoylation negatively regulates transcription in S. cerevisiae. We show that all four core histones are sumoylated and identify specific sites of sumoylation in histones H2A, H2B, and H4. We demonstrate that histone sumoylation sites are involved directly in transcriptional repression. Further, while histone sumoylation occurs at all loci tested throughout the genome, slightly higher levels occur proximal to telomeres. We observe a dynamic interplay between histone sumoylation and either acetylation or ubiquitylation, where sumoylation serves as a potential block to these activating modifications. These results indicate that sumoylation is the first negative histone modification to be identified in S. cerevisiae and further suggest that sumoylation may serve as a general dynamic mark to oppose transcription.


Assuntos
Histonas/metabolismo , Proteína SUMO-1/metabolismo , Saccharomyces cerevisiae/metabolismo , Acetilação , Sequência de Aminoácidos , Western Blotting , Imunoprecipitação , Processamento de Proteína Pós-Traducional , Saccharomyces cerevisiae/genética , Telômero , Ubiquitina/metabolismo
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