Sunday, April 26, 2015

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


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].


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.


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.

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. Effects of Dual Cyclooxygenase-2 and Carbonic Anhydrase Inhibition. NCT00780325 (retrieved on 26-04-2015)
5. Phase II Study of CG100649 for Primary Osteoarthritis in Male Subjects. NCT00530452 (retrieved on 26-04-2015)
6. Phase III Study of CG100649 in Osteoarthritis Patients. NCT01765296 (retrieved on 26-04-2015)