169280-71-1Relevant articles and documents
Design and synthesis of potent HIV-1 protease inhibitors with (S)-tetrahydrofuran-tertiary amine-acetamide as P2?ligand: Structure?activity studies and biological evaluation
Bai, Xiaoguang,Yang, Zhiheng,Zhu, Mei,Dong, Biao,Zhou, Lei,Zhang, Guoning,Wang, Juxian,Wang, Yucheng
, p. 30 - 44 (2017/05/31)
The design, synthesis, and SAR study of a new series of HIV-1 protease inhibitors incorporating stereochemically defined tetrahydrofuran-tertiary amine-acetamide P2-ligand are described. Various substituent effects on the tertiary amine P2-ligand and phenylsulfonamide P2′-ligand were investigated to maximize the ligand-binding site interactions in the protease active site. Most of inhibitors displayed low nanomolar to subnanomolar inhibitory potency. Inhibitor 20e containing N-(S-tetrahydrofuran)-N-(2-methoxyethyl)acetamide as P2-ligand along with 4-methoxylphenylsulfonamide as P2′-ligand displayed the most potent enzyme inhibitory activity (IC50 = 0.35 nM) and remarkably low cytotoxicity (CC50 = 305 μM).
Discovery and selection of TMC114, a next generation HIV-1 protease inhibitor
Surleraux, Dominique L. N. G.,Tahri, Abdellah,Verschueren, Wim G.,Pille, Geert M. E.,De Kock, Herman A.,Jonckers, Tim H. M.,Peeters, Anik,De Meyer, Sandra,Azijn, Hilde,Pauwels, Rudi,De Bethune, Marie-Pierre,King, Nancy M.,Prabu-Jeyabalan, Moses,Schiffer, Celia A.,Wigerinck, Piet B. T. P.
, p. 1813 - 1822 (2007/10/03)
The screening of known HIV-1 protease inhibitors against a panel of multi-drug-resistant viruses revealed the potent activity of TMC126 on drug-resistant mutants. In comparison to amprenavir, the improved affinity of TMC126 is largely the result of one extra hydrogen bond to the backbone of the protein in the P2 pocket. Modification of the substitution pattern on the phenylsulfonamide P2′ substituent of TMC126 created an interesting SAR, with the close analogue TMC114 being found to have a similar antiviral activity against the mutant and the wild-type viruses. X-ray and thermodynamic studies on both wild-type and mutant enzymes showed an extremely high enthalpy driven affinity of TMC114 for HIV-1 protease. In vitro selection of mutants resistant to TMC114 starting from wild-type virus proved to be extremely difficult; this was not the case for other close analogues. Therefore, the extra H-bond to the backbone in the P2 pocket cannot be the only explanation for the interesting antiviral profile of TMC114. Absorption studies in animals indicated that TMC114 has pharmacokinetic properties comparable to currently approved HIV-1 protease inhibitors.
Bis-amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
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Page column 55, (2008/06/13)
Selected bis-amino acid hydroxyethylamino sulfonamide compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease. The present invention relates to such retroviral protease inhibitors and, more particularly, relates to selected novel compounds, composition and method for inhibiting retroviral proteases, such as human immunodeficiency virus (HIV) protease, prophylactically preventing retroviral infection or the spread of a retrovirus, and treatment of a retroviral infection.
