Discovery of new potent molecular entities able to inhibit mPGES-1

Discovery of new potent molecular entities able to inhibit mPGES-1 mPGES-1, a glutathione-dependent membrane protein is involved in the last step of PGE2 production and has been well recognized as a strategic target for the development of anti-inflammatory and anti-cancer agents. It has been proven to selectively control the PGE2 levels induced by inflammatory stimuli, with neither affecting PGE2 constitutively produced, nor homeostatic prostanoids, so that its modulation can represent a better strategy to control PGE2 related disorders, compared to the use of the classical anti-inflammatory drugs, endowed with severe side effects. Despite the intensive research on the identification of potent mPGES-1 inhibitors as attractive candidates for drug development, none of the disclosed molecules, except for LY3023705, which recently entered clinical trials, are available for clinical use, therefore the discovery of new effective mPGES-1 inhibitors with increased drug–like properties are urgently needed. Continuing our work aimed at identifying new chemical platforms able to interact with this enzyme, here we describe the discovery of potent mPGES-1 modulators, featuring a 1-fluoro-2,4-dinitro-biphenyl-based scaffold, by processing and docking a small collection of synthetically accessible molecules, built around two main fragments, disclosed in our in silico screening. The top scoring hits obtained have been synthesized and tested, and five of the predicted compounds showed to potently inhibit mPGES-1 enzyme, without affecting COX enzymes activities. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Medicinal Chemistry Elsevier

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Publisher
Elsevier
Copyright
Copyright © 2017 Elsevier Masson SAS
ISSN
0223-5234
eISSN
1768-3254
D.O.I.
10.1016/j.ejmech.2017.10.039
Publisher site
See Article on Publisher Site

Abstract

mPGES-1, a glutathione-dependent membrane protein is involved in the last step of PGE2 production and has been well recognized as a strategic target for the development of anti-inflammatory and anti-cancer agents. It has been proven to selectively control the PGE2 levels induced by inflammatory stimuli, with neither affecting PGE2 constitutively produced, nor homeostatic prostanoids, so that its modulation can represent a better strategy to control PGE2 related disorders, compared to the use of the classical anti-inflammatory drugs, endowed with severe side effects. Despite the intensive research on the identification of potent mPGES-1 inhibitors as attractive candidates for drug development, none of the disclosed molecules, except for LY3023705, which recently entered clinical trials, are available for clinical use, therefore the discovery of new effective mPGES-1 inhibitors with increased drug–like properties are urgently needed. Continuing our work aimed at identifying new chemical platforms able to interact with this enzyme, here we describe the discovery of potent mPGES-1 modulators, featuring a 1-fluoro-2,4-dinitro-biphenyl-based scaffold, by processing and docking a small collection of synthetically accessible molecules, built around two main fragments, disclosed in our in silico screening. The top scoring hits obtained have been synthesized and tested, and five of the predicted compounds showed to potently inhibit mPGES-1 enzyme, without affecting COX enzymes activities.

Journal

European Journal of Medicinal ChemistryElsevier

Published: Jan 1, 2018

References

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