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1.
Antiviral Res ; 47(2): 121-9, 2000 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-10996400

RESUMO

AIDS therapies employing HIV protease inhibitors (PIs) are associated with changes in fat metabolism. However, the cellular mechanisms affected by PIs are not clear. Thus, the affects of PIs on adipocyte differentiation were examined in vitro using C3H10T1/2 stem cells. In these cells the PIs, nelfinavir, saquinavir, and ritonavir, reduced triglyceride accumulation, lipogenesis, and expression of the adipose markers, aP2 and LPL. Histological analysis revealed nelfinavir, saquinavir and ritonavir treatment decreased oil red O-staining of cytoplasmic fat droplets. Inhibition occurred in the presence of the RXR agonist LGD1069, indicating the inhibitory effects were not due to an absence of RXR ligand. Moreover, these three PIs increased acute lipolysis in adipocytes. In contrast, two HIV PIs, amprenavir and indinavir, had little effect on lipolysis, lipogenesis, or expression of aP2 and LPL. Although, saquinavir, inhibited ligand-binding to PPARgamma with an IC(50) of 12.7+/-3.2 microM, none of the other PIs bound to the nuclear receptors RXRalpha or PPARgamma, (IC(50)s>20 microM), suggesting that inhibition of adipogenesis is not due to antagonism of ligand binding to RXRalpha or PPARgamma. Taken together, the results suggest that some, but not all, PIs block adipogenesis and stimulate fat catabolism in vitro and this may contribute to the effects of PIs on metabolism in the clinic.


Assuntos
Adipócitos/metabolismo , Inibidores da Protease de HIV/farmacologia , Lipólise/efeitos dos fármacos , Proteínas de Neoplasias , Tiazolidinedionas , Triglicerídeos/metabolismo , Adipócitos/citologia , Animais , Compostos Azo/farmacologia , Bexaroteno , Carbamatos , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Corantes/farmacologia , Proteínas de Ligação a Ácido Graxo , Furanos , Indinavir/farmacologia , Insulina/farmacologia , Lipase Lipoproteica/genética , Lipase Lipoproteica/metabolismo , Nelfinavir/farmacologia , RNA Mensageiro/análise , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores do Ácido Retinoico/agonistas , Receptores do Ácido Retinoico/metabolismo , Receptores X de Retinoides , Ritonavir/farmacologia , Rosiglitazona , Saquinavir/farmacologia , Células-Tronco , Sulfonamidas/farmacologia , Tetra-Hidronaftalenos/farmacologia , Tiazóis/farmacologia , Fatores de Transcrição/agonistas , Fatores de Transcrição/metabolismo
2.
J Med Chem ; 41(25): 5020-36, 1998 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-9836620

RESUMO

We have identified a novel series of antidiabetic N-(2-benzoylphenyl)-L-tyrosine derivatives which are potent, selective PPARgamma agonists. Through the use of in vitro PPARgamma binding and functional assays (2S)-3-(4-(benzyloxy)phenyl)-2-((1-methyl-3-oxo-3-phenylpropenyl)+ ++amin o)propionic acid (2) was identified as a structurally novel PPARgamma agonist. Structure-activity relationships identified the 2-aminobenzophenone moiety as a suitable isostere for the chemically labile enaminone moiety in compound 2, affording 2-((2-benzoylphenyl)amino)-3-(4-(benzyloxy)phenyl)propionic acid (9). Replacement of the benzyl group in 9 with substituents known to confer in vivo potency in the thiazolidinedione (TZD) class of antidiabetic agents provided a dramatic increase in the in vitro functional potency and affinity at PPARgamma, affording a series of potent and selective PPARgamma agonists exemplified by (2S)-((2-benzoylphenyl)amino)-3-¿4-[2-(methylpyridin-2-ylamino+ ++)ethoxy ]phenyl¿propionic acid (18), 3-¿4-[2-(benzoxazol-2-ylmethylamino)ethoxy]phenyl¿-(2S)-((2- benzoylph enyl)amino)propanoic acid (19), and (2S)-((2-benzoylphenyl)amino)-3-¿4-[2-(5-methyl-2-phenyloxazol-4-y l)e thoxy]phenyl¿propanoic acid (20). Compounds 18 and 20 show potent antihyperglycemic and antihyperlipidemic activity when given orally in two rodent models of type 2 diabetes. In addition, these analogues are readily prepared in chiral nonracemic fashion from L-tyrosine and do not show a propensity to undergo racemization in vitro. The increased potency of these PPARgamma agonists relative to troglitazone may translate into superior clinical efficacy for the treatment of type 2 diabetes.


Assuntos
Aminopiridinas/síntese química , Proteínas de Ligação a DNA/agonistas , Hipoglicemiantes/síntese química , Hipolipemiantes/síntese química , Oxazóis/síntese química , Propionatos/síntese química , Receptores Citoplasmáticos e Nucleares/agonistas , Fatores de Transcrição/agonistas , Tirosina/análogos & derivados , Tirosina/síntese química , Administração Oral , Aminopiridinas/química , Aminopiridinas/farmacologia , Animais , Glicemia/metabolismo , Linhagem Celular , Diabetes Mellitus Experimental/sangue , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Ligantes , Lipídeos/biossíntese , Masculino , Camundongos , Oxazóis/química , Oxazóis/farmacologia , Propionatos/química , Propionatos/farmacologia , Ensaio Radioligante , Ratos , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteínas Recombinantes de Fusão/agonistas , Proteínas Recombinantes de Fusão/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismo , Transfecção , Tirosina/química , Tirosina/farmacologia
3.
J Med Chem ; 41(25): 5037-54, 1998 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-9836621

RESUMO

We previously reported the identification of (2S)-((2-benzoylphenyl)amino)-3-¿4-[2-(5-methyl-2-phenyloxazol-4-y l)e thoxy]phenyl¿propanoic acid (2) (PPARgamma pKi = 8.94, PPARgamma pEC50 = 9.47) as a potent and selective PPARgamma agonist. We now report the expanded structure-activity relationship around the phenyl alkyl ether moiety by pursuing both a classical medicinal chemistry approach and a solid-phase chemistry approach for analogue synthesis. The solution-phase strategy focused on evaluating the effects of oxazole and phenyl ring replacements of the 2-(5-methyl-2-phenyloxazol-4-yl)ethyl side chain of 2 with several replacements providing potent and selective PPARgamma agonists with improved aqueous solubility. Specifically, replacement of the phenyl ring of the phenyloxazole moiety with a 4-pyridyl group to give 2(S)-((2-benzoylphenyl)amino)-3-¿4-[2-(5-methyl-2-pyridin-4-yloxazol+ ++- 4-yl)ethoxy]phenyl¿propionic acid (16) (PPARgamma pKi = 8.85, PPARgamma pEC50 = 8.74) or a 4-methylpiperazine to give 2(S)-((2-benzoylphenyl)amino)-3-(4-¿2-[5-methyl-2-(4-methylpiperazin+ ++- 1-yl)thiazol-4-yl]ethoxy¿phenyl)propionic acid (24) (PPARgamma pKi = 8.66, PPARgamma pEC50 = 8.89) provided two potent and selective PPARgamma agonists with increased solubility in pH 7.4 phosphate buffer and simulated gastric fluid as compared to 2. The second strategy took advantage of the speed and ease of parallel solid-phase analogue synthesis to generate a more diverse set of phenyl alkyl ethers which led to the identification of a number of novel, high-affinity PPARgamma ligands (PPARgamma pKi's 6.98-8.03). The combined structure-activity data derived from the two strategies provide valuable insight on the requirements for PPARgamma binding, functional activity, selectivity, and aqueous solubility.


Assuntos
Proteínas de Ligação a DNA/agonistas , Hipoglicemiantes/síntese química , Hipolipemiantes/síntese química , Oxazóis/síntese química , Propionatos/síntese química , Receptores Citoplasmáticos e Nucleares/agonistas , Tiazóis/síntese química , Fatores de Transcrição/agonistas , Tirosina/análogos & derivados , Tirosina/síntese química , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Ligantes , Lipídeos/biossíntese , Camundongos , Oxazóis/química , Oxazóis/farmacologia , Propionatos/química , Propionatos/farmacologia , Ensaio Radioligante , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteínas Recombinantes de Fusão/agonistas , Proteínas Recombinantes de Fusão/metabolismo , Solubilidade , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacologia , Fatores de Transcrição/metabolismo , Transfecção , Tirosina/química , Tirosina/farmacologia
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