New aza-dipeptide analogues as potent and orally absorbed HIV-1 protease inhibitors: candidates for clinical development - PubMed (original) (raw)

. 1998 Aug 27;41(18):3387-401.

doi: 10.1021/jm970873c.

A Fässler, H G Capraro, R Cozens, T Klimkait, J Lazdins, J Mestan, B Poncioni, J Rösel, D Stover, M Tintelnot-Blomley, F Acemoglu, W Beck, E Boss, M Eschbach, T Hürlimann, E Masso, S Roussel, K Ucci-Stoll, D Wyss, M Lang

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New aza-dipeptide analogues as potent and orally absorbed HIV-1 protease inhibitors: candidates for clinical development

G Bold et al. J Med Chem. 1998.

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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