RESUMO
The synthesis of a new class of 9-(S)-dihydroerythromycin derivatives and their anti-inflammatory activity on in vivo PMA assay are described. Modifying the desosamine sugar on the C-3' amino group, it was possible to differentiate between anti-biotic and anti-inflammatory action. The compounds are completely devoid of anti-microbial effects but their anti-inflammatory properties are enhanced. These results strongly suggest the potential of macrolides as a new class of anti-inflammatory agents.
Assuntos
Amino Açúcares/química , Anti-Inflamatórios/uso terapêutico , Edema/tratamento farmacológico , Eritromicina/análogos & derivados , Eritromicina/uso terapêutico , Animais , Anti-Inflamatórios/síntese química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Desenho de Fármacos , Edema/patologia , Eritromicina/síntese química , Eritromicina/farmacologia , CamundongosRESUMO
This communication describes the synthesis and in vitro evaluation of a novel and potent series of phosphodiesterase type IV (PDE4) inhibitors. The compounds described present substituents in position 4 of the phthalazine ring to replace the commonly observed cyclopentyloxy moiety of rolipram analogues. Preliminary evidences of reduced side effects compared to standards and improved pharmacokinetic properties for selected derivatives are also reported.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Ftalazinas/síntese química , Ftalazinas/farmacologia , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Animais , Benzamidas/farmacologia , Disponibilidade Biológica , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Inibidores Enzimáticos/química , Cobaias , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/enzimologia , Ftalazinas/química , Ligação Proteica , Piridinas/farmacologia , Rolipram/metabolismo , Fator de Necrose Tumoral alfa/biossínteseRESUMO
A series of anti-HIV prodrugs possessing various polyaminated side arms have been developed. The incorporation of a N-Boc protected monoamine or diamine side arm into the backbone of the 2',3'-dideoxy-3'-thiacytidine 1 (BCH-189) provided an increase in antiviral potency, which could be several orders magnitude greater than the parent drug (1) depending on the cell culture systems used (MT-4 or MDMs). Twenty six 2',3'-dideoxy-3'-thiacytidine prodrugs which differ from each other by the length, the nature of the 5'-O function and the 5'-O or/and N-4 position on the nucleoside moiety were synthesized. Among this new series of prodrugs, several congeners (12c and 12a) were found to inhibit HIV-1 replication in cell culture with 50% effective concentrations EC50 of 10 and 50 nM respectively, in MT-4 cells. Compound 12c was found more active on infected MDMs cells with 50% effective concentration of 0.01 nM. The synthesis and the antiviral properties of these compounds are discussed.
Assuntos
Fármacos Anti-HIV/síntese química , Lamivudina/análogos & derivados , Lamivudina/síntese química , Pró-Fármacos/síntese química , Fármacos Anti-HIV/farmacologia , Diaminas/química , Humanos , Lamivudina/farmacologia , Macrófagos/metabolismo , Espectrometria de Massas , Pró-Fármacos/farmacologia , Células Tumorais CultivadasRESUMO
This communication describes the synthesis and in vitro evaluation of a novel and potent series of phosphodiesterase type IV (PDE4) inhibitors. The compounds described represent conformationally constrained analogues of RP 73401, Piclamilast. Preliminary evidences of reduced side effects of II compared to standards are also reported.
