br Conclusion To conclude it would be fair

Conclusion To conclude, it would be fair to say that the research efforts on FLAP inhibitors for intervening with LT biosynthesis have reached to a considerably advanced state during the last decade as a result of growing interest from both pharmaceutical industry and academia [4], [37], [38]. During that time, all evidence presented in the literature substantiated a key role of LTs in a variety of human diseases and justified the modulation of FLAP activity as a rational approach for prevention, treatment or amelioration of these inflammation-related disorders. More importantly, after the first demonstration of LTB4 in atherosclerotic plaques in 1988 [127], the wealth of compiled evidence has implicated a critical role for LTB4 in various phases of CVD and diverted the roadmap of LT research from allergic and respiratory diseases to CVD, highlighting the potential value of FLAP as a therapeutic target for CVD within the 5-LO cascade [2], [3]. During the past decade, the disclosure of the first three-dimensional structure of an integral membrane protein FLAP made certainly possible to conduct a rational structure-based design of novel inhibitor chemotypes more extensively [28], [36], [37], [128]. These developments along with the accumulated SAR data from early studies speeded up the drug discovery efforts and eventually resulted in development of several drug-like molecules such as GSK2190915/AM803, BI665915 and AZD6642, which were reported to be in various stages of preclinical and clinical studies for treatment of respiratory diseases such as Guanethidine Sulfate and COPD as well as CV disorders like atherosclerosis, as reviewed within this manuscript and elsewhere [4], [37], [38]. As a final remark, it can be seen within this review, the early FLAP inhibitor structures clearly evolved along the way from highly lipophilic and bigger molecules (i.e., Merck/Amira compounds) first to a medium size and lipophilicity, and then to a lower molecular weight and rather polar structures (i.e. Janssen compounds). This evolutionary SAR data in combination with the binding site knowledge from crystal structure might certainly change the way of look to the design approaches to discover novel and more drug-like FLAP inhibitors.
Introduction Despite advances in the management of trauma, shock, and postinjury critical care, post-traumatic lung injury leading to acute respiratory distress syndrome (ARDS) continues to result in compelling morbidity and high cost of care. Prior investigation has shown that lung dysfunction following trauma and hemorrhagic shock (T/HS) is exacerbated by the presence of proinflammatory molecules derived from arachidonic acid (AA). Specifically, postshock mesenteric lymph contains free AA that has been shown to activate the leukotriene biosynthetic pathway.2, 3, 4 The rate-limiting enzyme in this pathway is arachidonate lipoxygenase-5 (ALOX5), which ultimately results in the production of bioactive leukotrienes. The inhibition of the ALOX5 pathway has been shown to reduce lung damage following T/HS in a murine model. Arachidonate lipoxygenase-5 activating protein (ALOX5AP) is a cofactor of ALOX5 that is thought to have two primary roles: (1) potentiating ALOX5 catalysis and (2) anchoring complexed ALOX5/ALOX5AP to the nuclear membrane. In addition, selective inhibition of ALOX5AP attenuates leukotriene synthesis. Although recent evidence has suggested a mechanism for ALOX5/ALOX5AP binding at the nuclear membrane in the presence of AA, the role of the localized ALOX5/ALOX5AP complex in the development of lung injury after T/HS has not been firmly established. Furthermore, it is not known whether inhibition of ALOX5AP results in the inhibition of ALOX5/ALOX5AP association and colocalization. Finally, the inhibition of ALOX5/ALOX5AP association as a method to curtail the development of post-traumatic lung injury has not been explored. Therefore, we hypothesize that molecular association of ALOX5 and ALOX5AP is a necessary condition for the production of the proinflammatory leukotrienes that contribute to the development of post-traumatic lung injury.