Wednesday, January 13, 2016

Imrecoxib | NSAID | Treatment of Osteoarthritis | COX-2 Inhibitor

Imrecoxib [4-(4-methane-sulfonyl-phenyl)-1-propyl-3-p-tolyl-1,5-dihydropyrrol-2-one] is a novel and moderately selective cyclooxygenase-2 (COX-2) inhibitor that possesses anti-inflammatory effect by inhibition of COX-2 mRNA expression. It belongs to the family of non-steroid anti-inflammtory drugs (NSAIDs). Imrecoxib was found to inhibit COX-1 and COX-2 with IC50 value of 115 ± 28 nM and 18 ± 4 nM, respectively [1].
Imrecoxib: 2D and 3D Structure

Imrecoxib effectively inhibited carrageenan-induced acute inflammation at the doses of 5, 10, and 20 mg-kg-1 ig and adjuvant-induced chronic inflammation at the doses of 10 and 20 mg-kg -1·d-1 ig.

NSAIDs and Imrecoxib:

Non-steroidal anti-inflammatory drugs (NSAIDs) are used extensively for the treatment of inflammatory conditions, including pain-releasing, anti-pyretic and rheumatoid arthritis. These functions are believed to inhibit the enzyme cyclooxygenase (COX) that is involved in the biosynthesis of prostaglandins G and H from arachidonic acid. So far two isozymes of COX are known: COX-1 and COX-2. COX-1 is constitutively produced in a variety of tissues and appears to be important to the maintenance of normal physiological functions, including gastric and renal cytoprotection. The COX-2 is an inducible isozyme, which is produced in cells under the stimulation of endotoxins, cytokines, and hormones and catalyzes the production of prostaglandins which cause inflammation.

The currently therapeutic use of NSAIDs has been associated with the inhibition of both COX-1 and COX-2 and causes well-known side effects at the gastrointestinal and renal level. Therefore, the selective COX-2 inhibitors could provide anti-inflammatory agents devoid of the undesirable effects associated with classical, nonselective NSAIDs. In addition, COX-2 is over-expressed in colon cancer tissue. COX-2 inhibitors possess potential prophylactic and therapeutic application to colon cancer.

Imrecoxib is designed in a manner such that it has "moderate selectivity" for COX-2 over COX-1.  This balanced inhibition to both COX-1 and COX-2 was pursued to maintain the homeostasis of the two enzymes in the body,which is presumably critical to normal functions of the cardiovascular system.

Imrecoxib was launched in China with the trade name of Hengyang for the treatment of osteoarthritis in May 2011. Hengyang  is available as tablet for oral use, containing 100 mg of free Imrecoxib, and the recommend dose is 100 mg twice daily.

Summary Sheet

Common name: Imrecoxib; BAP-909; BAP 909; BAP909
Trademarks: Hengyang
Molecular Formula: C21H23NO3S
CAS Registry Number: 395683-14-4
IUPAC Name: 4-(4-methane-sulfonyl-phenyl)-1-propyl-3-p-tolyl-1,5-dihydropyrrol-2-one
Molecular Weight: 369.48
Mechanism: COX-2 Inhibitor; Cyclooxygenase-2 Inhibitor
Activity: Treatment of Osteoarthritis; Analgesic; Antipyritic; Antiinflammatory Drug
Status: Launched 2011 (China)
Originator: HengRui

Imrecoxib Synthesis
Chin Chem Lett 2001, 12, 775-778 (also Ref 2. This route is quoted as industrial method in various texts)

CN104193664A (an improvement here as Br is replaced with Cl)

US7112605B2 (primary reference for synthesis routes)


1H NMR (Estimated) for Imrecoxib

Experimental: 1H-NMR (CDCl3, TMS, 400MHz) 1.008 (3H, t, J = 7.2Hz), 1.701-1.756 (2H, m), 2.376 (3H, s), 3.078 (3H, s), 3.575 (2H, t, J = 7.2Hz), 4.317 (2H, s), 7. 175 (2H, d, J = 8.0Hz), 7.294 (2H, d, J = 8.0Hz), 7.505 (2H, t, J = 6.8Hz), 7.870 (2H, t, J = 6.8Hz)

Being a mild COX-2 inhibitor, it is expected not to cause any serious cardiovascular risks. Similarly, it should not have any serious gastrointestinal problems too, as it not a good inhibitor of COX-1. None of the reports though have listed any serious adverse event reported by patients in the clinical trials.

1. Cheng, G. F.; et. al. Imrecoxib: A novel and selective cyclooxygenase 2 inhibitor with anti-inflammatory effect. Acta Pharmacol Sin 2004, 25(7), 927-931.
2. Zhang, F.; et. al. Method for preparing imrecoxib. CN102206178A
3. Chao, W.; et. al. Synthesis method of imrecoxib. CN104193664A
4. Bai, A. P.; et. al. Synthesis and in vitro Evaluation of a New Class of Novel Cyclooxygenase-2 Inhibitors: 3, 4-diaryl-3-pyrrolin-2 ones. Chin Chem Lett 2001, 12, 775-7785.
5. Guo, Z. Discovery of imrecoxib. Chin J New Drugs 2012, 21, 223.
6. Guo, Z.; et. al. Sulfonyl-containing 3,4-diaryl-3-pyrrolin-2-ones, preparation method, and medical use thereof. US7112605B2