Selectivity in the Inhibition of HIV and FIV Protease: Inhibitory and Mechanistic Studies of Pyrrolidine-Containing .alpha.-Keto Amide and Hydroxyethylamine Core Structures

• Published in: Journal of the American Chemical Society Vol. 117; no. 48; pp. 11867 - 11878
• Main Authors: Slee, Deborah H, Laslo, Karen L, Elder, John H, Ollmann, Ian R, Gustchina, Alla, Kervinen, Jukka, Zdanov, Alexander, Wlodawer, Alexander, Wong, Chi-Huey
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.12.1995; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Multidisciplinary; feline immunodeficiency virus; human immunodeficiency virus; Physical Sciences; Science & Technology; PROTECTED AMINO-ACIDS; CATS; FELINE IMMUNODEFICIENCY VIRUS; PEPTIDES; DIKETONE; ESTER DERIVATIVES; INFECTION; PROTEINASES; EXPRESSION; RNA-POLYMERASE
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja00153a008

This paper describes the development of new pyrrolidine-containing alpha-keto amide and hydroxyethylamine core structures as mechanism based inhibitors of the HIV and FIV proteases. It was found that the alpha-keto amide core structure 2 is approximately 300-fold better than the corresponding hydroxyethylamine isosteric structure and 1300-fold better than the corresponding phosphinic acid derivative as an inhibitor of the HIV protease. The alpha-keto amide is however not hydrated until it is bound to the HIV protease as indicated by the NMR study and the X-ray structural analysis. Further analysis of the inhibition activities of hydroxyethylamine isosteres containing modified pyrrolidine derivatives revealed that a cis-methoxy group at C-4 of the pyrrolidine would improve the binding 5-and 25-fold for the trans-isomer. When this strategy was applied to the alpha-keto amide isostere, a cis-benzyl ether at C-4 was found to enhance binding 3-fold. Of the core structures prepared as inhibitors of the HIV protease, none show significant inhibitory activity against the mechanistically identical FIV protease, and additional complementary groups are needed to improve inhibition.