198904-22-2Relevant articles and documents
New aza-dipeptide analogues as potent and orally absorbed HIV-1 protease inhibitors: Candidates for clinical development
Bold, Guido,F?ssler, Alexander,Capraro, Hans-Georg,Cozens, Robert,Klimkait, Thomas,Lazdins, Janis,Mestan, Jürgen,Poncioni, Bernard,R?sel, Johannes,Stover, David,Tintelnot-Blomley, Marina,Acemoglu, Figan,Beck, Werner,Boss, Eugen,Eschbach, Martin,Hürlimann, Thomas,Masso, Elvira,Roussel, Serge,Ucci-Stoll, Katharina,Wyss, Dominique,Lang, Marc
, p. 3387 - 3401 (2007/10/03)
On the basis of previously described X-ray studies of an enzyme/aza- dipeptide complex, 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.