RESUMO
The thienopyridines class of drugs used as P2Y12 receptor antagonists plays a vital role in antiplatelet therapy. To further optimized this compound class, we designed and synthesized a series of amino acid prodrugs of 2-hydroxytetrahydrothienopyridine. All compounds were then evaluated for their inhibitory effect on ADP-induced platelet aggregation in rats and then ED50 and bleeding time of the most potent compounds were compared with commercial drugs. The results showed compound 5c could be a potent and safe candidate for further research.
Assuntos
Difosfato de Adenosina/efeitos adversos , Agregação Plaquetária/efeitos dos fármacos , Pró-Fármacos/administração & dosagem , Pró-Fármacos/síntese química , Tienopiridinas/química , Animais , Tempo de Sangramento , Clopidogrel , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Masculino , Estrutura Molecular , Cloridrato de Prasugrel/administração & dosagem , Cloridrato de Prasugrel/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Ratos , Ticlopidina/administração & dosagem , Ticlopidina/análogos & derivados , Ticlopidina/farmacologiaRESUMO
The multiple physiological properties of glucagon-like peptide-1 (GLP-1) make it a promising drug candidate for the treatment of type 2 diabetes. However, the in vivo half-life of GLP-1 is short due to rapid degradation by dipeptidyl peptidase-IV (DPP-IV) and renal clearance. The poor stability of GLP-1 has significantly limited its clinical utility; however, many studies are focused on extending its stability. Fatty acid conjugation is a traditional approach for extending the stability of therapeutic peptides because of the high binding affinity of human serum albumin for fatty acids. However, the conjugate requires a complex synthetic approach, usually involving Lys and occasionally involving a linker. In the current study, we conjugated the GLP-1 molecule with fatty acid derivatives to simplify the synthesis steps. Human serum albumin binding assays indicated that the retained carboxyl groups of the fatty acids helped maintain a tight affinity to HSA. The conjugation of fatty acid-like molecules improved the stability and increased the binding affinity of GLP-1 to HSA. The use of fatty acid-like molecules as conjugating components allowed variant conjugation positions and freed carboxyl groups for other potential uses. This may be a novel, long-acting strategy for the development of therapeutic peptides.