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

Wu, Xiongyu; Ohrngren, Per; Joshi, Advait A.; Trejos, Alejandro; Persson, Magnus; Arvela, Riina K.; Wallberg, Hans; Vrang, Lotta; Rosenquist, Asa and Samuelsson, Bertil B., et al. (2012) In Journal of Medicinal Chemistry 55(6). p.2724-2736
Abstract
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.... (More)
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). (Less)
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publication status
published
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Journal of Medicinal Chemistry
volume
55
issue
6
pages
2724 - 2736
publisher
American Chemical Society (ACS)
external identifiers
  • wos:000301767000017
  • scopus:84863342365
ISSN
1520-4804
DOI
10.1021/jm201620t
language
English
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yes
id
1204394a-db71-4ea3-bcb4-fb1439e5bd51 (old id 2591119)
date added to LUP
2012-05-29 11:04:14
date last changed
2017-01-01 03:59:28
@article{1204394a-db71-4ea3-bcb4-fb1439e5bd51,
  abstract     = {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).},
  author       = {Wu, Xiongyu and Ohrngren, Per and Joshi, Advait A. and Trejos, Alejandro and Persson, Magnus and Arvela, Riina K. and Wallberg, Hans and Vrang, Lotta and Rosenquist, Asa and Samuelsson, Bertil B. and Unge, Johan and Larhed, Mats},
  issn         = {1520-4804},
  language     = {eng},
  number       = {6},
  pages        = {2724--2736},
  publisher    = {American Chemical Society (ACS)},
  series       = {Journal of Medicinal Chemistry},
  title        = {Synthesis, X-ray Analysis, and Biological Evaluation of a New Class of Stereopure Lactam-Based HIV-1 Protease Inhibitors},
  url          = {http://dx.doi.org/10.1021/jm201620t},
  volume       = {55},
  year         = {2012},
}