RESUMO
On the basis of previously described X-ray studies of an enzyme/aza-dipeptide complex,8 aza-dipeptide analogues carrying N-(bis-aryl-methyl) substituents on the (hydroxethyl)hydrazine moiety have been designed and synthesized as HIV-1 protease inhibitors. By using either equally (12) or orthogonally (13) protected dipeptide isosteres, symmetrically and asymmetrically acylated aza-dipeptides can be synthesized. This approach led to the discovery of very potent inhibitors with antiviral activities (ED50) in the subnanomolar range. Acylation of the (hydroxethyl)hydrazine dipeptide isostere with the L-tert-leucine derivative 29 increased the oral bioavailability significantly when compared to the corresponding L-valine or L-isoleucine derivatives. The bis(L-tert-leucine) derivatives CGP 75355, CGP 73547, CGP 75136, and CGP 75176 combine excellent antiviral activity with high blood concentration after oral administration. Furthermore, they show no cross-resistance with saquinavir-resistant strains and maintain activity against indinavir-resistant ones. Consequently they qualify for further profiling as potential clinical candidates.
Assuntos
Fármacos Anti-HIV , Compostos Aza , Dipeptídeos , Inibidores da Protease de HIV , Protease de HIV/metabolismo , Administração Oral , Animais , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Compostos Aza/administração & dosagem , Compostos Aza/síntese química , Compostos Aza/farmacologia , Disponibilidade Biológica , Dipeptídeos/administração & dosagem , Dipeptídeos/síntese química , Dipeptídeos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Resistência Microbiana a Medicamentos , Feminino , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/farmacologia , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , HIV-1/fisiologia , Indinavir/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Saquinavir/farmacologia , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
A microbial screening indicated that two fungal strains, Beauveria bassiana DSM 1344=ATCC 7159 and Cunninghamella elegans DSM 1908=ATCC 9245, as well as four bacterial strains belonging to the genus Streptomyces were able to hydroxylate 4,5-dianilinophthalimide (DAPH, CGP52411) to 4-(4'-hydroxyanilino)-5-anilinophthalimide. Cunninghamella elegans DSM 1908 turned out to be the most active biocatalyst and was also able to form the dihydroxy derivative, 4,5-bis(4'-hydroxyanilino)phthalimide. The reaction for the monohydroxylated biotransformation product was carried out on a preparative scale, and the culture conditions for the formation of 4-(4'-hydroxy- anilino)-5-anilinophthalimide with this strain were op-timized.