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1.
Sci Transl Med ; 4(148): 148ra115, 2012 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-22914621

RESUMO

Nicotinic acid (niacin) induces beneficial changes in serum lipoproteins and has been associated with beneficial cardiovascular effects. Niacin reduces low-density lipoprotein, increases high-density lipoprotein, and decreases triglycerides. It is well established that activation of the seven-transmembrane G(i)-coupled receptor GPR109A on Langerhans cells results in release of prostaglandin D2, which mediates the well-known flushing side effect of niacin. Niacin activation of GPR109A on adipocytes also mediates the transient reduction of plasma free fatty acid (FFA) levels characteristic of niacin, which has been long hypothesized to be the mechanism underlying the changes in the serum lipid profile. We tested this "FFA hypothesis" and the hypothesis that niacin lipid efficacy is mediated via GPR109A by dosing mice lacking GPR109A with niacin and testing two novel, full GPR109A agonists, MK-1903 and SCH900271, in three human clinical trials. In mice, the absence of GPR109A had no effect on niacin's lipid efficacy despite complete abrogation of the anti-lipolytic effect. Both MK-1903 and SCH900271 lowered FFAs acutely in humans; however, neither had the expected effects on serum lipids. Chronic FFA suppression was not sustainable via GPR109A agonism with niacin, MK-1903, or SCH900271. We conclude that the GPR109A receptor does not mediate niacin's lipid efficacy, challenging the long-standing FFA hypothesis.


Assuntos
Ácidos Graxos/metabolismo , Niacina/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Receptores Nicotínicos/metabolismo , Animais , Relação Dose-Resposta a Droga , Ácidos Graxos/sangue , Humanos , Lipólise/efeitos dos fármacos , Lipoproteínas/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Niacina/administração & dosagem , Pirazóis/farmacologia , Receptores Acoplados a Proteínas G/agonistas
2.
J Med Chem ; 53(6): 2666-70, 2010 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-20184326
3.
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
4.
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
6.
Proc Natl Acad Sci U S A ; 103(17): 6682-7, 2006 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-16617107

RESUMO

Nicotinic acid (NA) is commonly used to treat dyslipidemia, but it elicits an adverse effect, termed flushing, which consists of cutaneous vasodilation with associated discomfort. An animal model of NA-induced flushing has been established in mice. As in humans, NA stimulated vasodilation in a dose-dependent manner, was associated with an increase of the vasodilatory prostaglandin (PG) D2 in plasma and could be blocked by pretreatment with aspirin. Two PGD2 receptors have been identified: PGD2 receptor 1 (DP1, also called DP) and PGD2 receptor 2 (DP2, sometimes termed CRTH2). DP2 does not mediate NA-induced vasodilation; the DP2-specific agonist DK-PGD2 (13,14-dihydro-15-keto-PGD2) did not induce cutaneous vasodilation, and DP2-/- mice had a normal vasodilatory response to NA. By contrast, BW245C, a DP1-selective agonist, induced vasodilation in mice, and MK-0524, a DP1-selective antagonist, blocked both PGD2- and NA-induced vasodilation. NA-induced vasodilation was also studied in DP1+/+, DP1+/-, and DP1-/- mice; although NA-induced vasodilation depended almost completely on DP1 in female mice, it depended only partially on DP1 in male mice. The residual NA-induced vasodilation in male DP-/- mice was aspirin-sensitive. Thus, in the mouse, DP1 appears to be an important component involved in NA-induced vasodilation, but other cyclooxygenase-dependent mechanisms also may be involved. A clinical study in healthy men and women demonstrated that treatment with MK-0524 reduced the symptoms of flushing and the increase in skin perfusion after the administration of NA. These studies suggest that DP1 receptor antagonism may be an effective means to suppress NA-induced flushing in humans.


Assuntos
Niacina/farmacologia , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia , Adolescente , Adulto , Animais , Aspirina/farmacologia , Feminino , Rubor/tratamento farmacológico , Rubor/fisiopatologia , Humanos , Hidantoínas/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Prostaglandina D2/análogos & derivados , Prostaglandina D2/farmacologia , Prostaglandina-Endoperóxido Sintases/fisiologia , Receptores Imunológicos/agonistas , Receptores Imunológicos/deficiência , Receptores Imunológicos/genética , Receptores de Prostaglandina/agonistas , Receptores de Prostaglandina/deficiência , Receptores de Prostaglandina/genética
7.
Atherosclerosis ; 181(2): 251-9, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16039278

RESUMO

Diabetes mellitus is one of the major risk factors associated with atherosclerosis and coronary heart disease but the mechanistic links between the disease and atherosclerosis are not well understood. In this study, we investigated the effect of the deletion of the long-form leptin receptor on the progression of atherosclerosis in ApoE-/- mouse. ApoE-/-;db/db double knockout mice as well as ApoE-/-;db/+ and ApoE-/- littermates were generated by crossing ApoE-/- and db/+ mice. On a regular chow diet, ApoE-/-;db/db mice at 20 weeks of age exhibited features typical of type 2 diabetes: obesity, hyperglycemia, hyperinsulinemia and dyslipidemia and had significantly accelerated atherosclerosis compared with their age-matched ApoE-/- littermates as assessed by either the percentage of the aorta bearing lesion (5.3+/-0.9% for ApoE-/-;db/db versus 1.5+/-0.5% for ApoE-/-) or by aortic lipid content ( approximately 1.5-2-fold increase in free cholesterol and approximately 3-4-fold increase in cholesteryl ester). The atherosclerosis in these ApoE-/-;db/db mice was further accelerated by feeding mice with a Western diet and markedly inhibited by fenofibrate with a 2.5- and 5.3-fold reduction of the lesion in male and female mice, respectively. The results from this study demonstrate that type 2 diabetes can accelerate atherogenesis in mice. This mouse model may provide insight into the mechanistic link between type 2 diabetes and atherosclerosis as well as serve as a valuable tool for evaluating therapeutics.


Assuntos
Apolipoproteínas E/genética , Aterosclerose/genética , Modelos Animais de Doenças , Hipercolesterolemia/genética , Camundongos Knockout , Receptores de Superfície Celular/genética , Animais , Aterosclerose/patologia , Aterosclerose/fisiopatologia , Colesterol/sangue , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/fisiopatologia , Angiopatias Diabéticas/genética , Angiopatias Diabéticas/patologia , Angiopatias Diabéticas/fisiopatologia , Feminino , Fenofibrato/farmacologia , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/fisiopatologia , Hipolipemiantes/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores para Leptina , Índice de Gravidade de Doença
8.
J Biol Chem ; 280(29): 26649-52, 2005 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-15929991

RESUMO

As a treatment for dyslipidemia, oral doses of 1-3 grams of nicotinic acid per day lower serum triglycerides, raise high density lipoprotein cholesterol, and reduce mortality from coronary heart disease (Tavintharan, S., and Kashyap, M. L. (2001) Curr. Atheroscler. Rep. 3, 74-82). These benefits likely result from the ability of nicotinic acid to inhibit lipolysis in adipocytes and thereby reduce serum non-esterified fatty acid levels (Carlson, L. A. (1963) Acta Med. Scand. 173, 719-722). In mice, nicotinic acid inhibits lipolysis via PUMA-G, a Gi/o-coupled seven-transmembrane receptor expressed in adipocytes and activated macrophages (Tunaru, S., Kero, J., Schaub, A., Wufka, C., Blaukat, A., Pfeffer, K., and Offermanns, S. (2003) Nat. Med. 9, 352-355). The human ortholog HM74a is also a nicotinic acid receptor and likely has a similar role in anti-lipolysis. Endogenous levels of nicotinic acid are too low to significantly impact receptor activity, hence the natural ligands(s) of HM74a/PUMA-G remain to be elucidated. Here we show that the fatty acid-derived ketone body (D)-beta-hydroxybutyrate ((D)-beta-OHB) specifically activates PUMA-G/HM74a at concentrations observed in serum during fasting. Like nicotinic acid, (D)-beta-OHB inhibits mouse adipocyte lipolysis in a PUMA-G-dependent manner and is thus the first endogenous ligand described for this orphan receptor. These findings suggests a homeostatic mechanism for surviving starvation in which (D)-beta-OHB negatively regulates its own production, thereby preventing ketoacidosis and promoting efficient use of fat stores.


Assuntos
Ácido 3-Hidroxibutírico/farmacologia , Adipócitos/metabolismo , Lipólise/efeitos dos fármacos , Agonistas Nicotínicos/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Animais , Linhagem Celular , Retroalimentação Fisiológica , Humanos , Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/farmacologia , Ligantes , Camundongos , Receptores Acoplados a Proteínas G
9.
Bioorg Med Chem Lett ; 12(5): 827-32, 2002 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-11859012

RESUMO

A series of 2-arylindoles containing novel heteroaromatic substituents on the tryptamine tether, based on compound 1, was prepared and evaluated for their ability to act as gonadotropin releasing hormone (GnRH) antagonists. Successful modifications of 1 included chain length variation (reduction) and replacement of the pyridine with heteroaromatic groups. These alterations culminated in the discovery of compound 27kk which had excellent in vitro potency and oral efficacy in rodents.


Assuntos
Fármacos para a Fertilidade Feminina/antagonistas & inibidores , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Indóis/farmacologia , Quinolinas/farmacologia , Triptaminas/química , Administração Oral , Animais , Sítios de Ligação , Busserrelina/metabolismo , Humanos , Indóis/administração & dosagem , Indóis/química , Fosfatos de Inositol/metabolismo , Hormônio Luteinizante/metabolismo , Masculino , Quinolinas/química , Ratos , Relação Estrutura-Atividade
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