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

• Published in: Scientific reports 2018-07, Vol.8 (1), p.10005-14, Article 10005
• Main Authors: Singh, Palwinder, Kaur, Jagroop, Kaur, Harpreet, Kaur, Anudeep, Bhatti, Rajbir
• Format: Article
• Language: English
• Subjects: 140/131; 631/154/309; 692/699/255; Acetic acid; Acids; Analgesia; Anti-inflammatory agents; Cancer; Cyclooxygenase-2; Diabetes mellitus; Enzymes; Experiments; Humanities and Social Sciences; Inflammation; Ligands; Metabolism; multidisciplinary; Neurodegenerative diseases; Pain perception; Pharmacokinetics; Science; Science (multidisciplinary); Therapeutic applications
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-28408-8

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.