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
SMILES: O=C1N(CCC)CC(C2=CC=C(S(=O)(C)=O)C=C2)=C1C3=CC=C(C)C=C3
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)

Identification:

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)

Sideeffects:

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.

References:

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

Drugs in Clinical Pipeline: CG100649

CG100649 [4-(3-(3-fluorophenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzenesulfonamide] demonstrates a dual mechanism of action on cyclooxygenase-2 (COX2) and carbonic anhydrase (CA) that may result in favorable treatment effects and few adverse gastrointestinal and cardiovascular events [1].

Cyclooxygenase-2 (COX-2) inhibitors have become a common analgesic treatment option for patients with arthritis. However, long-term treatment has been associated with increased cardiovascular risk. With the past withdrawals and rejections of approval for COX-2 inhibitors the treatment options are now very limited. This translates for example to about 10 million osteoarthritis patients in the US who cannot receive COX-2 inhibitors because of concomitant hypertension. And this exemplifies the unmet medical need to develop and offer safe treatment options for this particular patient population. Preclinical data show a dual mechanism of action, which consists of the inhibition of the two enzymes COX-2 and carbonic anhydrase-I/-II (CA-I/II) and through which the cardiovascular risk of COX-2 inhibition might be attenuated [4].

Common Name: CG100649

Synonyms:  CG100649; CG-100649; CG 100649; Polmacoxib

IUPAC Name: (4-(3-(3-fluorophenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzenesulfonamide

CAS Number: 301692-76-2

Mechanism of Action: Cyclooxygenase-2 Inhibitor; COX2 Inhibitor; Carbonic Anhydrase Inhibitor; CA Inhibitor; Analgesics; Antirheumatic Agents; Enzyme Inhibitors

Indication: Anti-inflammatory

Development Stage: Phase III

Company: Crystal Genomics, Inc. (South Korea)

In mouse models CG100649 inhibits premalignant and malignant colorectal lesions partly through inhibiting tumor cell proliferation. These pre-clinical findings suggest a need for further exploration of CG100649 for CRC prevention and treatment. The long-term safety profile of CG100649, particularly regarding its effect on cardiovascular risk, is yet to be determined [2].

Nonsteroidal anti-inflammatory drugs (NSAIDs) elevate cardiovascular risk by disrupting cyclooxygenase-2 (COX-2)-dependent biosynthesis of prostacyclin (PGI(2)). CG100649 is a novel NSAID proposed to inhibit both COX-2 and carbonic anhydrase (CA)-I/-II. Researchers compared its impact on prostanoid biosynthesis with that of celecoxib, an NSAID purposefully designed to selectively inhibit COX-2. In a controlled, double-blind randomized trial, single oral doses of 2 or 8 mg CG100649, 200 mg celecoxib, or placebo were well tolerated by healthy volunteers (n = 23). Both CG100649 and celecoxib had the effect of depressing urinary excretion of 2,3-dinor-6-keto-PGF(1a) (PGI-M); the effect of CG100649 was dose-dependent and more sustained (up to 240 h after the dose) than that of celecoxib. Neither CG100649 nor celecoxib significantly inhibited COX-1-dependent prostanoid formation. Carbonic Anhydrase (CA) inhibition was not detected after administration of CG100649, despite its partitioning asymmetrically into erythrocytes. CG100649 and celecoxib are both relatively selective inhibitors of COX-2, but they differ in duration of action. Whether they have similar impact on cardiovascular events remains to be determined [3].

Phase I Study

Methodology

In a randomized, double-blind, placebo-controlled, multiple ascending oral dose study that was performed on 8 male and 8 female subjects per dose cohort. Each subject was randomly selected to receive either a single loading dose followed by 6 days of once-daily placebo (n = 4; 2 male and 2 female subjects) or CG100649 (n = 12; 6 male and 6 female subjects). Each subject was administered 1 of 3 sequential dose levels (8-mg loading dose + 2 mg/d, 10-mg loading dose + 4 mg/d, or 12-mg loading dose + 8 mg/d). Blood samples for pharmacokinetic analysis were obtained =480 hours after the last dose. Blood samples for measuring serum thromboxane B2 (TXB2) and ex vivo lipopolysaccharide-stimulated prostaglandin E2 (PGE2) (markers of cyclooxygenase-1 and cyclooxygenase-2 activity, respectively) and urine samples for measuring prostanoid metabolites were collected =21 days after the last dose [1].

Results

During steady state, the median Tmax in blood and plasma after the last dose ranged from 3 to 10 hours and 3.5 to 7.3 hours, respectively. Mean terminal t½ values in blood and plasma ranged from 121 to 203 hours and 100 to 167 hours, respectively. Whole blood concentrations were 50 to 70 times higher than plasma concentrations in all 3 dose cohorts in both male and female subjects. Compared with baseline, serum TXB2 diminished by 68% to 91% at 8 hours after the administration of the last dose in all 3 cohorts (P less than 0.001). Ex vivo lipopolysaccharide-stimulated PGE2 was maximally inhibited (89%-96%; P less than 0.001) by all 3 dose levels on day 7. Urinary prostacyclin metabolite was inhibited by 64% (P less than 0.001) on day 7 (12-24 hours) but only by the highest CG100649 dose. There were no clinically significant drug-related changes in blood pressure between treatment groups. The most frequently encountered adverse events were aphthous stomatitis and dyspepsia.

Conclusion

CG100649 was well tolerated and demonstrated a whole blood concentration that is ~50 to 70 times higher than in plasma in these healthy subjects. CG100649 suppressed TXB2 and PGE2 at all 3 doses, and only the highest dose suppressed the urinary excretion of the urinary prostacyclin metabolite.

References:

1. Kim, M. J.; et. al. Pharmacokinetic, pharmacodynamic, and safety/tolerability profiles of CG100649, a novel COX-2 inhibitor: results of a phase i, randomized, multiple-dose study in healthy Korean men and women. Clin Ther 2015, 37(1), 197-210.

2. Kim, S. H.; et. al. CG100649, a novel COX-2 inhibitor, inhibits colorectal adenoma and carcinoma growth in mouse models. Invest New Drugs 2014, 32(6), 1105-1112.

3. Skarke, C.; et. al. Comparative impact on prostanoid biosynthesis of celecoxib and the novel nonsteroidal anti-inflammatory drug CG100649. Clin Pharmacol Ther 2012, 91(6), 986-993.

4. ClinicalTrials.gov Effects of Dual Cyclooxygenase-2 and Carbonic Anhydrase Inhibition. NCT00780325 (retrieved on 26-04-2015)

5. ClinicalTrials.gov Phase II Study of CG100649 for Primary Osteoarthritis in Male Subjects. NCT00530452 (retrieved on 26-04-2015)

6. ClinicalTrials.gov Phase III Study of CG100649 in Osteoarthritis Patients. NCT01765296 (retrieved on 26-04-2015)