RESUMO
(-)DRF 2725 (6) is a phenoxazine analogue of phenyl propanoic acid. Compound 6 showed interesting dual activation of PPAR alpha and PPAR gamma. In insulin resistant db/db mice, 6 showed better reduction of plasma glucose and triglyceride levels as compared to rosiglitazone. Compound 6 has also shown good oral bioavailability and impressive pharmacokinetic characteristics. Our study indicates that 6 has great potential as a drug for diabetes and dyslipidemia.
Assuntos
Glicemia/análise , Hipoglicemiantes/síntese química , Oxazinas/síntese química , Fenilpropionatos/síntese química , Receptores Citoplasmáticos e Nucleares/agonistas , Fatores de Transcrição/agonistas , Triglicerídeos/sangue , Animais , Disponibilidade Biológica , Complicações do Diabetes , Diabetes Mellitus/tratamento farmacológico , Hiperlipidemias/complicações , Hiperlipidemias/tratamento farmacológico , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Resistência à Insulina , Camundongos , Oxazinas/farmacocinética , Oxazinas/farmacologia , Fenilpropionatos/farmacocinética , Fenilpropionatos/farmacologia , Ratos , Ratos Wistar , EstereoisomerismoRESUMO
[reaction: see text] Phosphoramidite reagents of the naturally occurring modified nucleosides mcm(5)s(2)U and mcm(5)U were synthesized and along with pseudouridine were incorporated into 17-nucleotide lysine tRNA anticodon stem-loop domains. Standard RNA phosphoramidite coupling chemistry allowed us to systematically investigate the thermodynamic effects of nucleoside modification and to correlate thermodynamic trends with qualitative structure effects seen by NMR spectroscopy.
Assuntos
Anticódon , Nucleosídeos/química , RNA de Transferência de Lisina/síntese química , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Nucleosídeos/síntese química , Pseudouridina/química , RNA de Transferência de Lisina/química , TermodinâmicaRESUMO
Several thiazolidinedione derivatives having 5-hydroxy-2,3-dihydro-2, 2,4,6,7-pentamethylbenzofuran moieties and their 5-benzyloxy derivatives and 5-hydroxy-2,4,6,7-tetramethylbenzofuran moieties were synthesized and evaluated in db/db mice. Insertion of an N-Me group into the linker between thiazolidinedione and substituted benzofuran pharmacophores showed considerable improvement in their euglycemic activity. Further improvement has been observed when a pyrrolidine moiety is introduced in the structure to give 5-[4-[N-[3(R/S)-5-benzyloxy-2,3-dihydro-2,2,4,6, 7-pentamethylbenzofuran-3-ylmethyl]-(2S)-pyrrolidin-2- ylmethoxy]pheny lene]thiazolidine-2,4-dione (21a). At a 100 mg/kg/day dose of the maleate salt, compound 21a reduced the plasma glucose and triglyceride to the level of lean littermate, i.e. 8 +/- 1 mM, and is the most potent and efficacious compound reported in this series.
Assuntos
Hipoglicemiantes/síntese química , Hipolipemiantes/síntese química , Pirrolidinas/síntese química , Tiazóis/síntese química , Animais , Glicemia/metabolismo , Feminino , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Hipolipemiantes/química , Hipolipemiantes/farmacocinética , Hipolipemiantes/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pirrolidinas/química , Pirrolidinas/farmacocinética , Pirrolidinas/farmacologia , Ratos , Ratos Wistar , Receptores Citoplasmáticos e Nucleares/agonistas , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacocinética , Tiazóis/farmacologia , Fatores de Transcrição/agonistas , Triglicerídeos/sangueRESUMO
Several thiazolidinediones having antioxidant moities in their structural motif have been synthesised and evaluated for their euglycemic and hypolipidemic activities. A few of them have been found to be superior to troglitazone.
Assuntos
Antioxidantes/síntese química , Hipoglicemiantes/síntese química , Hipolipemiantes/síntese química , Tiazóis/síntese química , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Desenho de Fármacos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Indicadores e Reagentes , Camundongos , Camundongos Mutantes , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacologia , Triglicerídeos/sangueRESUMO
Of the 21 compounds evaluated for antiimplantation and abortifacient activities, compounds (A1, A2, A4 and B1) and compounds (C1, C2, D1 and D3) were found to exhibit 40% and 30% antiimplantation activity, respectively, in female rats when given orally on days 1-5 postcoitum. The remaining 13 compounds were found to be inactive. All of the 21 compounds were also tested for the abortifacient activity, but all were found to be inactive.
