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1.
J Med Chem ; 55(17): 7623-35, 2012 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-22873688

RESUMO

The activation by extracellular nucleotides of pancreatic P2Y receptors, particularly, the P2Y(1)R subtype, increases insulin secretion. Therefore, we developed analogues of the P2Y(1)R receptor agonist 2-MeS-ADP, as potential antidiabetic drugs. Analogue 3A was found to be a potent P2Y(1)R agonist (EC(50) = 0.038 µM vs 0.0025 µM for 2-MeS-ADP) showing no activity at P2Y(2/4/6)Rs. Analogue 3A was stable at pH 1.4 (t(1/2) = 7.3 h) and resistant to hydrolysis vs 2-MeS-ADP by alkaline phosphatase (t(1/2) = 6 vs 4.5 h), human e-NPP1 (4% vs 16% hydrolysis after 20 min), and human blood serum (30% vs 50% hydrolysis after 24 h). Intravenous administration of 3A in naive rats decreased blood glucose from 155 mg/dL to normal values, ca. 87 mg/dL, unlike glibenclamide, leading to subnormal values (i.e., 63 mg/dL). Similar observations were made for streptozotocin (STZ)-treated and db(+)/db(-) mouse models. Furthermore, 3A inhibits platelet aggregation in vitro and elongates bleeding time in mice (iv administration of 30 mg of 3A/kg), increasing bleeding time to 16 vs 9 min for Prasugrel. Oral administration of 30 mg/kg 3A to rats increased tail bleeding volume, similar to aspirin. These findings suggest that 3A may be an effective treatment for type 2 diabetes by reducing both blood glucose levels and platelet aggregation.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Agonistas do Receptor Purinérgico P2Y/química , Agonistas do Receptor Purinérgico P2Y/uso terapêutico , Animais , Glicemia/análise , Linhagem Celular Tumoral , Diabetes Mellitus Experimental/tratamento farmacológico , Teste de Tolerância a Glucose , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , Agonistas do Receptor Purinérgico P2Y/farmacologia , Ratos , Ratos Wistar
2.
J Med Chem ; 55(1): 437-48, 2012 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-22107038

RESUMO

Dinucleoside polyphosphates, Np(n)N', exert their physiological effects via P2 receptors (P2Rs). Np(n)N' are attractive drug candidates as they offer better stability and specificity compared to nucleotides, the most common P2R ligands. To further improve the agonist properties of Np(n)N', we synthesized novel isosters of dinucleoside polyphosphates where N and N' are A or U and where the Pα or Pß phosphate groups are replaced by boranophosphate, denoted as Np(n)(α-B)N' or Np(n)(ß-B)N' (n = 3, 4), respectively. The potency of Np(n)(α/ß-B)N' analogues was evaluated at tP2Y(1), hP2Y(2), hP2Y(4), and rP2Y(6) receptors. The most potent P2Y(1)R and P2Y(6)R agonists were the Up(4)(ß-B)A (A isomer, EC(50) of 0.5 µM vs 0.004 µM for 2-SMe-ADP) and Up(3)(α-B)U (B isomer, EC(50) of 0.3 µM vs 0.2 µM for UDP), respectively. The receptor subtype selectivity is controlled by the position of the borano moiety on the Np(n)N' polyphosphate chain and the type of the nucleobase. In addition, Np(n)(α/ß-B)N' proved ∼22-fold more resistant to hydrolysis by e-NPP1, as compared to the corresponding Np(n)N' analogues. In summary, Up(4)(ß-B)A and Up(3)(α-B)U are potent, stable, and highly selective P2Y(1) and P2Y(6) receptor agonists, respectively.


Assuntos
Boranos/síntese química , Fosfatos de Dinucleosídeos/síntese química , Agonistas do Receptor Purinérgico P2Y/síntese química , Receptores Purinérgicos P2Y/metabolismo , Animais , Boranos/química , Boranos/farmacologia , Cálcio/metabolismo , Linhagem Celular Tumoral , Fosfatos de Dinucleosídeos/química , Fosfatos de Dinucleosídeos/farmacologia , Estabilidade de Medicamentos , Humanos , Hidrólise , Modelos Moleculares , Conformação Molecular , Diester Fosfórico Hidrolases/química , Agonistas do Receptor Purinérgico P2Y/química , Agonistas do Receptor Purinérgico P2Y/farmacologia , Pirofosfatases/química , Estereoisomerismo , Relação Estrutura-Atividade , Turquia
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