Pharmacology of PF-4191834, a Novel, Selective Non-Redox 5-Lipoxygenase Inhibitor Effective in Inflammation and Pain

Abstract

5-Lipoxygenase (LOX) is an important arachidonic acidmetabolizing enzyme producing leukotrienes and other proinflammatory lipid mediators with potent pathophysiological functions in asthma and other inflammatory diseases. 4-(3-(4-(1-Methyl-1H-pyrazol-5-yl)phenylthio)phenyl)-tetrahydro-2H-pyran-4-carboxamide (PF-4191834) is a novel, selective non-redox 5-lipoxygenase inhibitor effective in inflammation and pain. In vitro and in vivo assays were developed for the evaluation of a novel 5-LOX inhibitor using conditions of maximal enzyme activity. PF-4191834 exhibits good potency in enzyme-and cell-based assays, as well as in a rat model of acute inflammation. Enzyme assay results indicate that PF-4191834 is a potent 5-LOX inhibitor, with an IC 50 ϭ 229 Ϯ 20 nM. Furthermore, it demonstrated ϳ300-fold selectivity for 5-LOX over 12-LOX and 15-LOX and shows no activity toward the cyclooxygenase enzymes. In addition, PF-4191834 inhibits 5-LOX in human blood cells, with an IC 80 ϭ 370 Ϯ 20 nM. This inhibitory concentration correlates well with plasma exposures needed for in vivo efficacy in inflammation in models of inflammatory pain. The combination of potency in cells and in vivo, together with a sustained in vivo effect, provides PF-4191834 with an overall pharmacodynamic improvement consistent with once a day dosing.The 5-lipoxygenase (LOX) pathway is thought to play an important role in the pathophysiology of asthma and other inflammatory diseases by controlling the production of several key inflammatory mediators (Harris et al., 1995;Rastogi and McHowat, 2006;Peters-Golden and Henderson, 2007;Rubin and Mollison, 2007). 5-LOX is required for the production of leukotrienes C 4 , D 4 , and E 4 (collectively known as the cysteinyl leukotrienes; cys-LTs), which are potent bronchoconstrictors and proinflammatory mediators. Cys-LTs are generated after5-LOX metabolism of arachidonic acid (AA) to form leukotriene (LT)A 4 . Another enzyme, LTC 4 synthase, present in several cells, including eosinophils, basophils, and mast cells, conjugates LTA 4 to glutathione to yield LTC 4 . LTC 4 is further metabolized into LTD 4 and LTE 4 (Samuelsson, 1987). The 5-LOX enzyme is also involved in the production of LTB 4 , a primary attractant and activator for leukocytes. This lipid is primarily synthesized in neutrophils and macrophages where the enzyme LTA 4 hydrolase converts LTA 4 to the potent chemoattractant LTB 4 (Samuelsson, 1987). 5-LOX activity also results in the production of bioactive metabolites 5-hydroxyeicosatetraenoic acid (HETE) and 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxoETE) (Miller et al., 2000;Powell and Rokach, 2005). 5-oxoETE has been shown to induce tissue eosinophilia; thus, it may play a role in asthma and other diseases (Stamatiou et al., 1998;Guilbert et al., 1999;Muro et al., 2003).The clinical importance of the leukotriene pathway in inflammatory airway disease is demonstrated by the efficacy of various agents in the treatment of asthma and allergic rhinitis. Cysteinyl leukotriene receptor 1 anta...

5-Lipoxygenase Inhibitors Attenuate TNF-α-Induced Inflammation in Human Synovial Fibroblasts

“…5-LOX inhibitor, NDGA is reported to attenuate ovalbumin-induced lung inflammation in rats [48]. Oral administration with PF-4191834, which is developed by Pfizer, is able to ameliorate arthritis-associated pain and inflammation in rat model [11]. In addition, lecofelone, a COX/5-LOX inhibitor is reported to inhibit the progress of osteoarthritis [49].…”

“…5-LOX is required for the production of leukotrienes (LTC4, LTD4, and LTE4) which are reported to be potent broncho-constrictors and proinflammatory mediators [11]. These leukotrienes are known as the cysteinly leukotrienes (cys-LTs).…”

“…PF-4191834, a novel selective 5-LOX inhibitor developed by Pfizer, is found to decrease arthritis-associated pain and inflammation in rat model [11]. However, the detailed mechanism of 5-LOX involved in inflammatory arthritis is still unclear.…”

Esculetin reduces leukotriene B4 level in plasma of rats with adjuvant-induced arthritis

“…The selective 5-LOX inhibitor zileuton inhibited LTB4 production by 70% in patients with RA in a randomized double blind placebo-controlled study [21]. The lipoxygenase inhibitor PF-4191834 developed by Pfizer was able to reduce pain and inflammation in an adjuvant-induced arthritis model in rats [22]. …”

A Fluorescence-Based Assay for Measuring the Redox Potential of 5-Lipoxygenase Inhibitors

“…CAY10606 is also predicted to be redox-active, based on the fact that it is more potent than its derivative, which lacks redox moiety [16]. PF4191834 is a non-redox 5-LO inhibitor [17]. Overall, five of the eight selected compounds are known to have redox activity.…”