Licofelone-A Novel Analgesic and Anti-Inflammatory Agent

Abstract

Dual inhibitors that block both cyclooxygenase (COX) and lipoxygenase (LOX) metabolic pathways of arachidonic acid are expected to possess clinical advantages over the selective inhibitors of COX enzyme. One of the most promising compounds belonging to this category is licofelone ([2,2 -dimethyl -6-(4-chloropheny-7-phenyl-2,3-dihydro-1H-pyrrazoline-5-yl] acetic acid). Originally discovered by Merckle GmbH and developed by EuroAllaince, licofelone (IC(50) COX=0.21 microM, IC(50) 5-LOX=0.18 microM) possesses significant analgesic, anti-inflammatory, and antiasthmatic effects at doses that cause no gastrointestinal (GI) side effects. The pharmacodynamic profile of licofelone has been assessed and compared with widely used NSAIDs in different animal models. The ED(50) value of licofelone is reported to be 11.22-27.07 mg/kg, po and 39.5-55-8 mg/kg, po against carrageenan-induced paw oedema and Randal Selitto hyperalgesic assay in rats, respectively. Licofelone showed analgesic effect (ED(50) = 31.33 mg/kg) against acetic acid-induced writhing in mice. Licofelone has long duration of action and more effective than indomethacin and zileuton with ED(50) values of 2.92 mg/kg, po and 36.77 mg/kg, po, in the mechanical hyperalgesia and cold allodynia testing, respectively, against rat model of incisional pain. Licofelone significantly ameliorated indomethacin-induced gastric ulceration, neutrophil adhesion in mesentery, and lipid peroxides in rat gastric mucosa. Also, licofelone reversed the altered vascular permeability, morphological changes, and prevented NSAIDs-related increase in leukotriene levels in gastric mucosa. The preclinical studies have shown that licofelone not only has convincing pharmacodynamic effect but also it is well tolerated. It is currently under clinical evaluation in osteoarthritis (OA), the most common form of arthritis. The present review describes pharmacological and clinical development of licofelone as a dual inhibitor.

Licofelone Suppresses Prostaglandin E2 Formation by Interference with the Inducible Microsomal Prostaglandin E2 Synthase-1

“…Licofelone is an advanced dual inhibitor of the COX and 5-lipoxygenase pathway, exhibiting not only a remarkable efficacy as anti-inflammatory drug but also exerting significantly less adverse effects under chronic use that are usually associated with NSAIDs (i.e., gastrointestinal injury and renal irritations) or selective COX-2 inhibitors (cardiovascular risks) (Kulkarni and Singh, 2007). Our data show that licofelone is a direct and potent inhibitor of COX-1 in cell-free assays, confirming previous conclusions drawn from analysis of the compound in cell-based test systems (Laufer et al, 1994b;Tries et al, 2002b).…”

“…There is accumulating evidence that inhibition of both the leukotriene and the PG biosynthetic pathway is superior over single interference, not only in terms of anti-inflammatory effectiveness but also due to a lower incidence of gastrointestinal toxicity, typically related to COX inhibition (Celotti and Laufer, 2001;Kulkarni and Singh, 2007). In fact, licofelone markedly improved gastrointestinal tolerability in animal models and offered gastroprotection against NSAIDs-induced gastropathy (Wallace et al, 1994;Kulkarni and Singh, 2007).…”

“…1A] is an anti-inflammatory drug that inhibits the COX and 5-lipoxygenase pathway and is currently undergoing phase III trials for osteoarthritis (for review, see Celotti and Laufer, 2001;Kulkarni and Singh, 2007). The effectiveness of licofelone has been demonstrated in animal models as well as in studies on humans, and it is attributed mainly to the efficient suppression of PGE 2 formation (Kulkarni and Singh, 2007).…”

“…1A] is an anti-inflammatory drug that inhibits the COX and 5-lipoxygenase pathway and is currently undergoing phase III trials for osteoarthritis (for review, see Celotti and Laufer, 2001;Kulkarni and Singh, 2007). The effectiveness of licofelone has been demonstrated in animal models as well as in studies on humans, and it is attributed mainly to the efficient suppression of PGE 2 formation (Kulkarni and Singh, 2007). It is interesting to note that in contrast to NSAIDs and selective COX-2 inhibitors, licofelone shows an improved gastrointestinal and potentially cardiovascular safety (Bias et al, 2004;Rotondo et al, 2006;Vidal et al, 2007).…”

In Vitro Metabolism of 2-[6-(4-Chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl] Acetic Acid (Licofelone, ML3000), an Inhibitor of Cyclooxygenase-1 and -2 and 5-Lipoxygenase

“…The mechanism of action of licofelone (i.e., inhibition of both COX-1/-2 and 5-LOX) was shown in pharmacological studies and in experimental disease models (Tries et al, 2002;Kulkarni and Singh, 2007). Human and veterinary clinical trials confirmed the efficacy of licofelone for treatment of osteoarthritis (Alvaro-Gracia, 2004;Moreau et al, 2007), as well as its advantageous gastrointestinal tolerability (Bias et al, 2004;Moreau et al, 2005).…”