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  • Title: New aza-dipeptide analogues as potent and orally absorbed HIV-1 protease inhibitors: candidates for clinical development.
    Author: Bold G, Fässler A, Capraro HG, Cozens R, Klimkait T, Lazdins J, Mestan J, Poncioni B, Rösel J, Stover D, Tintelnot-Blomley M, Acemoglu F, Beck W, Boss E, Eschbach M, Hürlimann T, Masso E, Roussel S, Ucci-Stoll K, Wyss D, Lang M.
    Journal: J Med Chem; 1998 Aug 27; 41(18):3387-401. PubMed ID: 9719591.
    Abstract:
    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.
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