1区 · 医学
Article
作者: Fässler, Alexander ; Lang, Marc ; Beck, Werner ; Boss, Eugen ; Poncioni, Bernard ; Stover, David ; Masso, Elvira ; Acemoglu, Figan ; Mestan, Jürgen ; Bold, Guido ; Wyss, Dominique ; Lazdins, Janis ; Klimkait, Thomas ; Capraro, Hans-Georg ; Cozens, Robert ; Tintelnot-Blomley, Marina ; Eschbach, Martin ; Roussel, Serge ; Rösel, Johannes ; Hürlimann, Thomas ; Ucci-Stoll, Katharina
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.
