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Synthesis, X-ray Analysis, and Biological Evaluation of a New Class of Stereopure Lactam-Based HIV-1 Protease Inhibitors

  • Xiongyu Wu
  • Per Ohrngren
  • Advait A. Joshi
  • Alejandro Trejos
  • Magnus Persson
  • Riina K. Arvela
  • Hans Wallberg
  • Lotta Vrang
  • Asa Rosenquist
  • Bertil B. Samuelsson
  • Johan Unge
  • Mats Larhed
Publiceringsår: 2012
Språk: Engelska
Sidor: 2724-2736
Publikation/Tidskrift/Serie: Journal of Medicinal Chemistry
Volym: 55
Nummer: 6
Dokumenttyp: Artikel i tidskrift
Förlag: American Chemical Society (ACS)


In an effort to identify a new class of druglike HIV-1 protease inhibitors, four different stereopure beta-hydroxy gamma-lactam-containing inhibitors have been synthesized, biologically evaluated, and cocrystallized. The impact of the tether length of the central spacer (two or three carbons) was also investigated. A compound with a shorter tether and (3R,4S) absolute configuration exhibited high activity with a K-i of 2.1 nM and an EC50 of 0.64 mu M. Further optimization by decoration of the P1' side chain furnished an even more potent HIV-1 protease inhibitor (K-i = 0.8 nM, EC50 = 0.04 mu M). According to X-ray analysis, the new class of inhibitors did not fully succeed in forming two symmetric hydrogen bonds to the catalytic aspartates. The crystal structures of the complexes further explain the difference in potency between the shorter inhibitors (two-carbon spacer) and the longer inhibitors (three-carbon spacer).


  • Medicinal Chemistry


  • ISSN: 1520-4804

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