New Aza-Dipeptide Analogues as Potent and Orally Absorbed HIV-1 Protease Inhibitors: Candidates for Clinical Development
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...
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Veröffentlicht in: | Journal of medicinal chemistry 1998-08, Vol.41 (18), p.3387-3401 |
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Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | 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. |
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ISSN: | 0022-2623 1520-4804 |
DOI: | 10.1021/jm970873c |