Synergy of Physico-chemical and Biological Experiments for Developing a Cyclooxygenase-2 Inhibitor

The physiological consequences of COX-2 overexpression in the development of cancer, diabetes and neurodegenerative diseases have made this enzyme a promising therapeutic target. Herein, COX-2 active site was analyzed and new molecules were designed. We identified a highly potent molecule (S)-3a wit...

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Autores principales: Singh, Palwinder, Kaur, Jagroop, Kaur, Harpreet, Kaur, Anudeep, Bhatti, Rajbir
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6030096/
https://www.ncbi.nlm.nih.gov/pubmed/29968808
http://dx.doi.org/10.1038/s41598-018-28408-8
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author Singh, Palwinder
Kaur, Jagroop
Kaur, Harpreet
Kaur, Anudeep
Bhatti, Rajbir
author_facet Singh, Palwinder
Kaur, Jagroop
Kaur, Harpreet
Kaur, Anudeep
Bhatti, Rajbir
author_sort Singh, Palwinder
collection PubMed
description The physiological consequences of COX-2 overexpression in the development of cancer, diabetes and neurodegenerative diseases have made this enzyme a promising therapeutic target. Herein, COX-2 active site was analyzed and new molecules were designed. We identified a highly potent molecule (S)-3a with IC(50) value and the selectivity for COX-2 0.6 nM and 1666, respectively. The MTD of (S)-3a was 2000 mg kg(−1) and its pharmacokinetic studies in rat showed t(1/2) 7.5 h. This compound reversed acetic acid induced analgesia and carragennan induced inflammation by 50% and 25% in rat when used at a dose 10 mg kg(−1). Mechanistically, it was found that compound (S)-3a inhibits COX-2. Overall, the combination of physico-chemical and biological experiments facilitated the development of a new lead molecule to anti-inflammatory drug.
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spelling pubmed-60300962018-07-11 Synergy of Physico-chemical and Biological Experiments for Developing a Cyclooxygenase-2 Inhibitor Singh, Palwinder Kaur, Jagroop Kaur, Harpreet Kaur, Anudeep Bhatti, Rajbir Sci Rep Article The physiological consequences of COX-2 overexpression in the development of cancer, diabetes and neurodegenerative diseases have made this enzyme a promising therapeutic target. Herein, COX-2 active site was analyzed and new molecules were designed. We identified a highly potent molecule (S)-3a with IC(50) value and the selectivity for COX-2 0.6 nM and 1666, respectively. The MTD of (S)-3a was 2000 mg kg(−1) and its pharmacokinetic studies in rat showed t(1/2) 7.5 h. This compound reversed acetic acid induced analgesia and carragennan induced inflammation by 50% and 25% in rat when used at a dose 10 mg kg(−1). Mechanistically, it was found that compound (S)-3a inhibits COX-2. Overall, the combination of physico-chemical and biological experiments facilitated the development of a new lead molecule to anti-inflammatory drug. Nature Publishing Group UK 2018-07-03 /pmc/articles/PMC6030096/ /pubmed/29968808 http://dx.doi.org/10.1038/s41598-018-28408-8 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Singh, Palwinder
Kaur, Jagroop
Kaur, Harpreet
Kaur, Anudeep
Bhatti, Rajbir
Synergy of Physico-chemical and Biological Experiments for Developing a Cyclooxygenase-2 Inhibitor
title Synergy of Physico-chemical and Biological Experiments for Developing a Cyclooxygenase-2 Inhibitor
title_full Synergy of Physico-chemical and Biological Experiments for Developing a Cyclooxygenase-2 Inhibitor
title_fullStr Synergy of Physico-chemical and Biological Experiments for Developing a Cyclooxygenase-2 Inhibitor
title_full_unstemmed Synergy of Physico-chemical and Biological Experiments for Developing a Cyclooxygenase-2 Inhibitor
title_short Synergy of Physico-chemical and Biological Experiments for Developing a Cyclooxygenase-2 Inhibitor
title_sort synergy of physico-chemical and biological experiments for developing a cyclooxygenase-2 inhibitor
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6030096/
https://www.ncbi.nlm.nih.gov/pubmed/29968808
http://dx.doi.org/10.1038/s41598-018-28408-8
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