RESUMO
The discovery of second generation N-hydroxyurea 5-lipoxygenase inhibitors was accomplished through the development of a broad structure-activity relationship (SAR) study. This study identified requirements for improving potency and also extending duration by limiting metabolism. Potency could be maintained by the incorporation of heterocyclic templates substituted with selected lipophilic substituents. Duration of inhibition after oral administration was optimized by identification of structural features in the proximity of the N-hydroxyurea which correlated to low in vitro glucuronidation rates. Furthermore, the rate of in vitro glucuronidation was shown to be stereoselective for certain analogs. (R)-N-[3-[5-(4-Fluorophenoxy)-2-furyl]-1-methyl-2-propynyl]-N-hydroxyure a (17c) was identified and selected for clinical development.
Assuntos
Inibidores Enzimáticos/síntese química , Hidroxiureia/análogos & derivados , Inibidores de Lipoxigenase , Animais , Células Cultivadas , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Furanos , Glucuronatos/metabolismo , Humanos , Macaca fascicularis , Modelos Químicos , Ratos , Relação Estrutura-Atividade , Moldes Genéticos , TiofenosRESUMO
Novel analogs of (9R)-9-deoxo-9-(N,N-dimethylamino)erythromycin A bearing N-alkylamino substituents at the C-21 position were synthesized. These compounds retained antibacterial activity. The C-21, N,N-dimethylamino analog showed a modest improvement in activity against some Gram-negative bacteria.
Assuntos
Eritromicina/análogos & derivados , Bactérias/efeitos dos fármacos , Eritromicina/síntese química , Eritromicina/farmacologia , Relação Estrutura-AtividadeRESUMO
Selective protection of (9R)-9-amino-9-deoxoerythromycin A allowed for elimination of the 12-hydroxyl group to afford a versatile 12,21-olefin intermediate. Further modifications of the intermediate led to the syntheses of (9R)-9-deoxo-9-(N,N-dimethylamino)-12,21-epoxyerythromycin B, (9R)-9-deoxo-9-(N,N-dimethylamino)-21-hydroxyerythromycin A, and (9R)-9-deoxo-9-(N,N-dimethylamino)-21-hydroxyerythromycin B. All three compounds retained antibacterial activity against several organisms normally susceptible to (9R)-9-deoxo-9-(N,N-dimethylamino)erythromycin A. However, the 21-hydroxylated erythromycin A analogue was weaker in potency than the corresponding erythromycin B congener and much weaker than the epoxy derivative. This suggests that while substitution of a polar functionality at C-21 does not abolish antibacterial activity, introduction of vicinal polar groups at both C-12 and C-21 may lead to reduction in potency. Nevertheless, these 21-functionalized derivatives of (9R)-erythromycylamine provide an entry into novel analogues of the important macrolide antibiotic erythromycin.
