Opportunities and Challenges for Fatty Acid Mimetics in Drug

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Opportunities and Challenges for Fatty Acid Mimetics in Drug Discovery Ewgenij Proschak,* Pascal Heitel, Lena Kalinowsky, and Daniel Merk* Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Straße 9, 60438 Frankfurt, Germany S Supporting Information *

ABSTRACT: Fatty acids beyond their role as an endogenous energy source and storage are increasingly considered as signaling molecules regulating various physiological effects in metabolism and inflammation. Accordingly, the molecular targets involved in formation and physiological activities of fatty acids hold significant therapeutic potential. A number of these fatty acid targets are addressed by some of the oldest and most widely used drugs such as cyclooxygenase inhibiting NSAIDs, whereas others remain unexploited. Compounds orthosterically binding to proteins that endogenously bind fatty acids are considered as fatty acid mimetics. On the basis of their structural resemblance, fatty acid mimetics constitute a family of bioactive compounds showing specific binding thermodynamics and following similar pharmacokinetic mechanisms. This perspective systematically evaluates targets for fatty acid mimetics, investigates their common structural characteristics, and highlights demands in their discovery and design. In summary, fatty acid mimetics share particularly favorable characteristics justifying the conclusion that their therapeutic potential vastly outweighs the challenges in their design.

1. INTRODUCTION Fatty acids are present in our body as nutritional contents, secondary metabolites, essential signaling molecules, and as an energy source. They are directly or indirectly involved in virtually every process of our physiology and, therefore, interact with a wide variety of proteins. Fatty acid mimetics structurally resemble fatty acids and are ligands of the fatty acid binding site in proteins that endogenously interact with fatty acids. The panel of potential pharmacological targets for fatty acid mimetics is very large, comprising nuclear hormone receptors, surface receptors, and enzymes. With growing knowledge of our physiology and identification of novel signaling cascades, the number of fatty acid targets is expected to increase further, and there are already numerous examples of successful agents targeting fatty acid receptors or fatty acid metabolizing enzymes, some of which are among our most widely used drugs. Because fatty acid mimetics target the orthosteric binding site of fatty acids in proteins, they are endowed with a panel of specific characteristics derived from their natural templates. Fatty acid mimetics structurally resemble naturally occurring fatty acids in their negative charge and dipolar architecture with a polar head and lipophilic tail. Consequently, fatty acid mimetics also share pharmacological characteristics such as pharmacokinetic behavior with their natural templates and face specific challenges. With increasing knowledge of the metabolic and inflammatory roles of nutritional and endogenously formed fatty acids, fatty acid mimetics constantly gain relevance and hold significant pharmacological potential. Hence, the ther© 2017 American Chemical Society

apeutic opportunities of fatty acid mimetics are at least as high as the challenges they face.

2. TARGETS FOR FATTY ACID MIMETICS 2.1. Nuclear Receptors. Fatty acids are essential physiological activators of several nuclear receptors (Table 1), i.e., the peroxisome proliferator-activated receptors (PPAR) α, γ, and δ, the retinoid X receptors (RXR) α, ,β and γ, the retinoic acid receptors (RAR) α, β, and γ, and in a broader sense, the farnesoid X receptor (FXR). These nuclear receptors act as ligand-activated transcription factors and are crucially involved in metabolism, energy expenditure, and inflammation. The activation of nuclear receptors causes induction or repression of the receptor’s target genes, which leads to a slow but durable and extensive cellular response.1 2.1.1. Peroxisome Proliferator-Activated Receptors (PPARs). PPARs are a group of three distinct nuclear receptors that are activated by unsaturated fatty acids and eicosanoids including prostaglandins. The receptors are major regulators of lipid and glucose metabolism and have a long history as drug targets. PPARs rarely act alone but require a retinoid X receptor as a heterodimer partner to act as ligand-activated transcription factors. As such, the PPARs each regulate a wide variety of target genes involved in metabolism and inflammation.2−4 PPARα is mainly found in tissues associated with intense fatty acid catabolism (brown adipose tissue, liver, heart, kidney, Received: August 25, 2016 Published: March 2, 2017 5235

DOI: 10.1021/acs.jmedchem.6b01287 J. Med. Chem. 2017, 60, 5235−5266

Journal of Medicinal Chemistry

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Table 1. Nuclear Receptors Activated by Fatty Acids and Fatty Acid Metabolites fatty acid mimetics that reached clinical use or clinical trials nuclear receptor

endogenous ligands

effects/role

PPARα

eicosanoids, unsat. fatty acids energy homeostasis, fatty acid catabolism

PPARγ PPARδ RXRs

eicosanoids, unsat. fatty acids glucose homeostasis, insulin sensitivity, anti-inflammatory eicosanoids, unsat. fatty acids energy homeostasis, thermogenesis, cell proliferation, tissue repair unknown heterodimer partner, proliferation, differentiation, apoptosis, inflammation all-trans-retinoic acid, growth/development, proliferation, differentiation, apoptosis, retinoids inflammation bile acids (CDCA) bile acid homeostasis, lipid/glucose metabolism, (liver) inflammation

RARs FXR

intestine) where it promotes fatty acid β-oxidation and gluconeogenesis. It is considered as a major regulator of nutrient metabolism in the fasting state and controls energy homeostasis. Accordingly, fibrates, agonists of PPARα, are effective lipid-lowering drugs. The dual PPARα/γ agonist saroglitazar is marketed in India for the treatment of type 2 diabetes mellitus and dyslipidemia. In addition, PPARα is discussed as a potential target for inflammatory disorders and to control obesity. A dual PPARα/δ agonist (elafibranor) is currently being evaluated in clinical trials for the treatment of nonalcoholic steatohepatitis and resulted in robust weight lowering effects.2−6 PPARγ expression is high in adipose tissues, skeletal muscle, liver, intestine, brain, and immune cells. The receptor has an important role in regulation of glucose homeostasis and insulin sensitivity, exerts anti-inflammatory effects, and controls adipocyte differentiation. Because of the crucial role in glucose metabolism, agonists of PPARγ such as the thiazolidindiones (glitazones) exhibit robust antidiabetic effects. However, although this indication for PPARγ agonists has recently lost some importance, many new beneficial effects of PPARγ modulation have been discovered. PPARγ could evolve as a target for the treatment of inflammatory disorders such as multiple sclerosis, inflammatory bowel disease, and arthritis as well as Alzheimer’s disease.2−4,7 PPARδ displays the widest tissue distribution among the PPARs but is highly expressed in brain, adipose tissue, skeletal muscle, and skin. PPARδ is also involved in the regulation of energy homeostasis, thermogenesis, and fatty acid catabolism but beyond that has a crucial role in cell proliferation and tissue repair. Numerous beneficial effects of PPARδ activation such as body weight reduction, insulin sensitization, and antiinflammatory activity have been discovered. Still, PPARδ is the only PPAR subtype not addressed by a marketed drug.2−4,8 2.1.2. Retinoid X Receptors (RXRs). The three retinoid X receptors RXRα, RXRβ, and RXRγ possess a particularly important role among nuclear receptors because they constitute the heterodimer partners of many other nuclear receptors including PPARs, liver X receptors (LXRs), retinoic acid receptors (RARs), farnesoid X receptor (FXR), thyroid hormone receptors (TRs), and vitamin D receptor (VDR). Although most of these heterodimers are permissive, meaning that they can be activated by an agonist of either partner, there are also nonpermissive heterodimers such as RXR-RAR and RXR-VDR that require an agonist of both partners to initiate target gene transcription. In addition to this extraordinary role as heterodimer partners, RXRs also act as monomers or

NR agonists

NR antagonists

fibrates, saroglitazar, elafibranor glitazones, saroglitazar elafibranor alitretinoin, bexarotene tazarotene, adapalene obeticholic acid

homodimers and regulate proliferation, differentiation, inflammation, and apoptosis.1,9−11 Although they are encoded by different genes, all RXR subtypes share high sequence identity (RXRα to RXRβ: 60.9%; RXRα to RXRγ: 69.4%; RXRβ to RXRγ: 57.6%) and are equally capable of heterodimer formation but differ in their expression pattern. RXRα is expressed in liver, intestine, kidney, lung, skeletal muscle, and skin; RXRβ is found ubiquitously, and RXRγ expression is limited to the central nervous system (CNS), heart, and skeletal muscle. Because RXR is required as a heterodimer partner, every cell of our body possesses at least one RXR subtype.1,9−11 RXRs are activated by several fatty acids with different potencies, and 9-cis-retinoic acid with nanomolar affinity (Kd ≈ 9−12 nM) constitutes the most potent fatty acid on RXRs known so far. Additionally, arachidonic acid, oleic acid, palmitoleic acid, docosahexaenoic acid, linoleic acid, and linolenic acid are weak RXR agonists with micromolar potency.10 Although several naturally occurring fatty acids are known to activate RXRs, a definite physiological RXR agonist remains to be discovered. The agonists mentioned above occur in too low physiological concentrations (9-cis-retinoic acid: Kd ≈ 9−12 nM, physiological concentrations LTC4 > LTE4

chemotaxis, phagocytosis, inflammation, (airway) hyperresponsiveness chemotaxis, angiogenesis, inflammation bronchoconstriction, chemotaxis, (pulmonary) inflammation

CysLT2

LTC4 ≥ LTD4 > LTE4

GPR31 GPR32

12(S)-HETE RvD1

ChemR23 ALX

chemerin, RvE1 LXA4, RvD1

secretion, tasting,

GPCR antagonists

fasiglifam

secretion, energy secretion, energy secretion, laropiprant, vidupiprant

seratrodast, terutroban

pranlukast, zafirlukast, montelukast

(pulmonary) inflammation, chemotaxis, vasoconstriction, vascular permeability ↑ pro-resolution, reduced expression of IL-1β and IL-8, macrophage polarization, enhanced phagocytosis pro-inflammatory and pro-resolution effects, metabolic balance pro-inflammatory and pro-resolution effects, upregulation of anti-inflammatory IL-10, reduced ROS production

cells and cause enhanced permeability, edema formation, vasoconstriction, and bronchoconstriction. Because CysLT antagonists are effective drugs in asthma treatment, LTC4S inhibition might similarly prevent bronchoconstriction and allergic edema formation.25,26,33 12-LO and 15-LO convert arachidonic acid to hydroperoxyeicosatetraenoic acids (12(S)-HPETE, 12(R)-HPETE, and 15(S)-HPETE), which are subsequently reduced to hydroxyeicosatetraenoic acids (12(S)-HETE, 12(R)-HETE, and 15(S)-HETE). HPETEs and HETEs also account for a significant fraction of endogenous arachidonic acid metabolites, and particularly, 12(S)-HETE has important physiological roles. It is involved in inflammation, the regulation of platelet function and aggregation, and possibly in the promotion of cancer. Several endogenous binding sites for 12(S)-HETE are discussed, including the orphan GPCR GPR31. 15(S)-HETE might have a role in vascular endothelial and smooth muscle cell function as well as in inflammation, but its endogenous function and targets are not characterized well. Furthermore, HETEs have been reported to activate PPARs.34,35 Lipoxygenases not only metabolize arachidonic acid but also utilize other polyunsaturated fatty acids such as linoleic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) as substrates generating an enormous variety of lipid mediators including specialized proresolving mediators (SPMs). The resolvins (RvD series from DHA and RvE series from EPA) formed by lipoxygenases (and partly by aspirinmodified COX-2) from the ω-3 fatty acids EPA and DHA play

converted to LTA4, which is a precursor for all other leukotrienes and is hydrolyzed to LTB4 by LTA4 hydrolase (LTA4H) or conjugated with cysteine by LTC4 synthase (LTC4S) to form LTC4. LTC4 is the precursor of LTD4 and LTE4 and, therefore, initiates the formation of cysteinyl leukotrienes.25,26,31,32 Leukotrienes activate specific G-protein-coupled receptors mediating pro-inflammatory effects and chemotaxis. The fatty acid derivatives play important roles in allergic reactions and asthma as well as in many inflammatory diseases. Therefore, 5LO inhibition holds great therapeutic potential, such as zileuton, a 5-LO inhibitor being a marketed drug for asthma treatment. Additionally, 5-LO inhibitors have been evaluated in several clinical trials for chronic obstructive pulmonary disease (COPD), atherosclerosis, and cardiovascular disease treatment. Constraining 5-LO product formation by inhibition of 5lipogenase activating protein (FLAP) is also within the focus of some drug development programs.25,26,33 However, entirely blocking leukotriene formation might, similarly to COX inhibition, generate several adverse effects, and more selective approaches might be superior. LTB4 via BLT1 and BLT2 receptors predominantly acts as a chemotactic agent recruiting neutrophils, eosinophils, and macrophages and induces the release of cytokines from inflammatory cells. Inhibition of LTA4H is therefore considered as a valuable experimental anti-inflammatory strategy. The cysteinyl leukotrienes LTC4, LTD4, and LTE4 via CysLT1 and CysLT2 receptors merely affect the endothelium and smooth muscle 5239



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incretins such as glucagon-like peptide 1 (GLP-1) and glucosedependent insulinotropic peptide (gastric inhibitory polypeptide (GIP)) in intestine and to promote glucose-stimulated insulin secretion in the pancreas. Thereby, FFARs have direct and indirect insulinotropic effects. Additionally, FFAR1 is crucially involved in testing of LCFAs and seems to have a role in inflammation. The SCFA receptor FFAR2 was found to promote energy expenditure and inhibit fat accumulation. Additionally, the receptor seems important for intestinal barrier and immunity function as well as for sensing SCFAs from intestinal microbiota connecting inflammation and metabolic balance with metabolites from the microbiome. Similarly, FFAR3 is highly expressed in the intestine and might be an important link between gut microbiota and metabolism as well as inflammation. Furthermore, FFAR3 is found throughout the sympathetic nervous system where it seems to affect heart rate and whole body energy expenditure. FFAR4 like FFAR1 has anti-inflammatory effects as it suppresses Toll-like receptor (TLR) and tumor necrosis factor α (TNFα) signaling in macrophages and seems important for differentiation and maturation of adipocytes. Genetic defects in FFAR4 that compromise activation by LCFAs are associated with obesity in humans.41,42 Whereas FFARs GPR40, GPR41, GPR43, and GPR120 are involved in sensing free fatty acids in metabolic balance and energy homeostasis, another G-protein-coupled receptor for fatty acids, GPR84, predominantly has a role in inflammation. It is expressed in bone marrow and in leukocytes as well as in monocytes and exclusively recognizes MCFAs with 9−14 carbon chain lengths.41,42 In light of their multitude of activities, FFARs seem to be valuable drug targets, especially for the treatment of metabolic diseases such as type 2 diabetes mellitus and obesity. SCFA receptors FFAR2 and FFAR3 may have a role as antiinflammatory targets as well because these receptors seem significantly involved in intestinal immunity. However, the wide variety of effects may also generate several adverse effects that could hinder FFAR targeting drug discovery.41,42 2.3.2. Prostaglandin Receptors. Prostaglandin receptors mediate most effects of arachidonic acid metabolites of the cyclooxygenase (COX) pathway. In two catalytic steps, COX-1 and COX-2 convert arachidonic acid to prostaglandin H2 (PGH2), which is subsequently transformed to PGD2, PGE2, PGF2α, PGI2, and TXA2 by specific synthases. All these arachidonic acid metabolites of the COX pathway comprise fatty acids and activate specific G-protein-coupled receptors. There are two distinct receptors D1 and D2 (also referred to as chemoattractant receptor-homologous molecule expressed on T-helper 2 cells (CRTh2)) for PGD2 and four distinct subtypes of EP (EP1, EP2, EP3, and EP4) receptors for PGE2, each encoded by a different gene. Only one receptor subtype each has been discovered for PGF2α (FP), TXA2 (TP), and PGI2 (IP). For FP (FPA, FPB) and TP (TPα, TPβ), two respective splice variants were reported. The variety of prostaglandin receptors for distinct fatty acid metabolites is primarily involved in inflammation and pain. FPs and TPs additionally play a role in cardiovascular homeostasis. The receptors strongly differ in expression pattern and signaling cascades and mediate effects of arachidonic acid metabolites in different body compartments.43−45 Motivated by the vast number of adverse effects resulting from COX inhibition, large efforts in the academic and industrial sector have been spent on the development of

important roles in the resolution of inflammation. Resolvins exert their anti-inflammatory and pro-resolving effects among others via GPCRs such as ChemR23, GPR32, BLT1, and the lipoxin receptor ALX. The 15-LO metabolite 17(S)-hydroperoxydocosahexaenoic acid (17(S)-HPDHA) is also a precursor of the protectins that are coinvolved in inflammation resolution and in neuroprotection.34,36,37 2.2.2.3. The CYP Pathway. As a third pathway, arachidonic acid is transformed to hydroxyeicosatrienoic acids (HETEs) by ω-hydroxylases (CYP4A enzymes) and to epoxyeicosatrienoic acids (EETs) by epoxygenases (CYP2C and CYP2J enzymes). The soluble epoxide hydrolase (sEH) subsequently converts EETs to the corresponding dihydroxyeicosatrienoic acids. The dominant CYPA4 metabolite 20-HETE constitutes a strong vasoconstrictor, whereas vasodilatory activity has been attributed to EETs. Additionally, EETs have robust antiinflammatory effects, prevent platelet-aggregation, and might have antihyperalgesic activity. The epoxides act mainly in the endothelium, but so far, a molecular target(s) mediating their beneficial effects has not been discovered. Eventually, EETs prevent the amplification of pro-inflammatory stimuli in the endothelium. As the corresponding DHETs do not display such valuable effects, inhibition of sEH, which causes accumulation of EETs, seems a very promising therapeutic strategy in inflammatory disorders and is currently attracting considerable attention. sEH inhibition has been implicated in various inflammatory diseases, neuropathic pain, cancer, and metabolic syndrome.25,26,38 2.3. G-Protein-Coupled Receptors. Nutritional signaling of fatty acids via G-protein-coupled receptors (GPCRs) has evolved as a highly studied topic in recent years. With the identification of at least four receptors for free fatty acids, namely, the free fatty acid receptors FFAR1 (GPR40), FFAR2 (GPR43), FFAR3 (GPR41), and FFAR4 (GPR120), many valuable new insights in metabolic balance and regulation have been discovered. However, activity of fatty acids on GPCRs is not limited to FFARs but also covers all target proteins of arachidonic acid metabolites with the prostaglandin receptors and leukotriene receptors, which are crucially involved in various inflammatory and anti-inflammatory processes. Additionally, the orphan GPCRs GPR84 and GPR119 are activated by some fatty acids, and the Takeda G-protein receptor 5 (TGR5) constitutes the membrane receptor for bile acids (Table 3). 2.3.1. Free Fatty Acid Receptors (FFARs). So far, four distinct G-protein-coupled receptors for free fatty acids have been discovered, namely, FFAR1 (GPR40), FFAR2 (GPR43), FFAR3 (GPR41), and FFAR4 (GPR120). The receptors distinguish between short chain fatty acids (SCFAs; ≤6 carbon atoms), medium chain fatty acids (MCFAs; 7−12 carbon atoms), and long chain fatty acids (LCFAs; ≥12 carbon atoms). FFAR2 and FFAR3 are activated by SCFAs, whereas FFAR4 recognizes MCFAs as well as LCFAs and FFAR1 activation is limited to LCFAs. FFAR1 and FFAR4 are also activated by several unsaturated fatty acids such as palmitoleic and docosahexaenoic acid. Notably, free fatty acids display rather weak potency on FFARs with EC50 values ranging from low micromolar to low millimolar concentrations.41,42 FFARs were generally found in various tissues and organs and seem to play a significant role in metabolic balance and energy homeostasis. However, among each other, the receptors display distinct expression patterns and signal via different pathways. All FFARs were found to induce the release of 5240



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predominantly caused by neutrophils and T-cells instead of eosinophils. Respective clinical trials are ongoing.46,47 In addition to BLTs and CysLTs, leukotrienes also activate a number of other receptors. LTB4 is a potent agonist of the nuclear receptor PPARα and activates the ligand-gated cation channel vanilloid transient receptor potential V1 receptor (TRPV1). Current data also suggest that LTE4, which is only a weak agonist of CysLTs but the most abundant cysteinyl leukotriene, activates another receptor that has not been firmly identified so far.46,47 2.3.4. Receptors for Anti-Inflammatory, Pro-Resolving Lipid Mediators. In the recent past, anti-inflammatory, proresolving lipid mediators derived from arachidonic acid and omega-3-fatty acids such as DHA have attracted considerable attention, and three GPCRs for these fatty acid metabolites have been identified so far. The lipoxin A4 receptor (also termed formyl peptide receptor type 2 (ALX/FPR2)) binds LXA4, RvD1, annexin, and several peptides involved in inflammatory regulation. ALX/FPR2 is present on leukocytes, macrophages, and intestinal epithelial cells and is involved in inflammatory as well as in resolution signaling, which might be dependent on ligand concentrations and dimerization with partner receptors. ALX/FPR2 activation has been reported to upregulate anti-inflammatory IL-10 formation, but attempts to target the receptor with an agonist failed due to receptor downregulation and desensitization.48−50 LXA4 and RvD1 (as well as other resolvins of the D series) also interact with GPR32, which has been identified on macrophages. The GPCR is involved in the resolution of inflammation, and its activation was reported to enhance phagocytosis and regulate polarization of macrophages.46,51,52 Two GPCRs binding RvE1 have been described so far. By inhibiting the BLT1 receptor and activating ChemR23, the resolvin has a dual mode of anti-inflammatory, pro-resolving activity. Chemokine-like receptor 1 (CMKLR1, ChemR23) was found on platelets, immature dendritic cells, resident macrophages, and natural killer cells, but its existence on other immune cells is uncertain. Furthermore, the receptor is expressed in adipose tissue and on smooth muscle cells. Activation of ChemR23 was reported to suppress macrophage activation and recruitment of neutrophils and monocytes, but the receptor is also involved in pro-inflammatory signaling. It has been proposed that binding of different ligands (different chemerin isoforms and RvE1) induces different conformations of ChemR23 that transduce distinct signals into the cell. In addition to regulation of inflammatory processes, ChemR23 seems to also affect metabolic balance, cardiovascular homeostasis, and cancer development.46,53−55 2.3.5. Fatty Acid Binding Proteins. Fatty acid binding proteins (FABPs), also referred as lipid chaperones, are 14−15 kDa intracellular proteins that reversibly bind saturated and unsaturated fatty acids as well as diverse lipid mediators.56 The FABP family is comprised of nine members with diverse expression patterns across different tissues. Under certain conditions, FABPs are able to enter the nucleus and transfer their ligands to lipid-activated nuclear receptors.57 Furthermore, FABPs are known to prolong the half-life of unstable lipid mediators such as LTA4 and facilitate their transport to enzymes.58 Notably, several fatty acid mimetics such as bezafibrate and ibuprofen bind to FABPs59 and are transported to their target proteins by FABPs. Because of the important roles in lipid trafficking and signaling, FABPs play important

selective agents targeting individual prostaglandin receptors. These fatty acid mimetics are thought to be less prone to unwanted effects as only single prostanoid pathways are modulated. This strategy has not replaced NSAIDs as the most clinically relevant agents targeting prostaglandin signaling so far. Still, prostaglandin receptors are promising targets for the treatment of various inflammatory and allergic diseases, cardiovascular diseases, as well as pain. However, exploiting prostaglandin receptors as drug targets also bears the risk of considerable side effects because all prostanoid receptor subtypes exhibit various physiological effects ranging from pro- to anti-inflammatory and from analgesic to antithrombotic activities.43,44 2.3.3. Leukotriene Receptors. In addition to COXs, 5lipoxygenase (5-LO), 12-LO, and 15-LO account for significant conversion of arachidonic acid to fatty acid metabolites. 5-LO with the help of 5-LO activating protein (FLAP) transforms arachidonic acid to leukotriene A4 (LTA4) and thereby initiates the 5-LO pathway. Similar to PGH2 in the COX pathway, the precursor LTA4 is then further converted by a cascade of enzymes to the leukotrienes LTB4, LTC4, LTD4, and LTE4. The latter three metabolites contain a cysteine moiety and are classified as cysteinyl leukotrienes.32 Leukotrienes interact with distinct G-protein-coupled receptors that are divided into the group of leukotriene B4 receptors (BLT) and the cysteinyl leukotriene receptors (CysLT) recognizing LTC4, LTD4, and LTE4. BLT receptors comprise two subtypes, BLT1 and BLT2, with significantly different expression patterns. BLT1 is mainly present on several leukocytes and lymphocytes where it regulates chemotaxis, tissue recruitment, and the release of immune mediators. In addition, BLT1 was found in the cardiovascular system in vascular smooth muscle cells and endothelial cells causing vasoconstriction and endothelial activation. In contrast, spleen, liver, and ovaries comprise the highest BLT2 expression, but the receptor is found nearly ubiquitously. Both BLT receptors are activated by LTB4, but the leukotriene has significantly higher affinity for BLT1 than for BLT2. Additionally, BLT2 can be activated by several other metabolites of the arachidonic acid cascade, whereas for BLT1, only a few ligands other than LTB4 are known. BLT receptors have been considered as drug targets for the treatment of several inflammatory diseases such as multiple sclerosis, inflammatory bowel disease, and pulmonary inflammation as well as atherosclerosis and cancer. To date, no BLT targeting fatty acid mimetic has reached the market.46,47 Cysteinyl leukotriene receptors CysLT1 and CysLT2, in contrast, have a long and successful history as clinically relevant drug targets in asthma. CysLT1 is especially activated by LTD4 and to a lesser extent by LTC4, and LTE4 comprises only a partial agonist. The receptor is found in different splice variants in leukocytes, peripheral blood mononuclear cells, spleen, thymus, lung, heart, and airway smooth muscle cells. Concerning CysLT2, the leukotrienes LTC4 and LTD4 possess equal agonistic potency, and LTE4 behaves as a partial agonist. CysLT2 is found in monocytes and endothelial cells. For their crucial role in eosinophil recruitment and activation in asthma as well as atopy, CysLTs are exploited as drug targets by the CysLT antagonists pranlukast, zafirlukast, and montelukast. Recent data suggest that CysLTs might also hold potential as a target in allergic rhinitis and other allergic disorders as well as in cardiovascular diseases. Furthermore, COPD patients might benefit from CysLT antagonists because COPD also involves a chronic inflammatory process in the airways, although it is 5241



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Kd, or Ki below 10 μM. These compounds were compared to drugs and random compounds from ChemblDB (Figure 2; details in Supporting Information).

physiological and pathophysiological roles in lipid metabolism and inflammation. Different FABPs have been the focus of drug discovery efforts. FABP4, also known as adipocyte FABP (A-FABP, aP2), has been related to diabetes, atherosclerosis, and inflammation. The selective inhibitor of A-FABP, BMS309403, reduced atherosclerotic lesions in ApoE−/− mice as well as inflammatory mediators related to obesity in ob/ob mice.60 Recent studies have additionally reported antiangiogenic and tumor suppressing activity of siRNA-mediated knockdown of FABP4 in vivo.61

3. CHEMISTRY 3.1. Basic Structure and Geometry of Fatty Acid Mimetics. Typical binding sites in nuclear or membrane receptors as well as enzymes accommodating fatty acids usually consist of a hydrophilic region responsible for carboxylate recognition and a hydrophobic cleft binding the alkyl chain. Fatty acid metabolizing enzymes usually contain a catalytic center located in the hydrophobic region. Thus, it is obvious that canonical fatty acid mimetics consist of an acidic headgroup connected to a hydrophobic residue filling the hydrophobic cleft. In several cases, the volume of the fatty acid binding site is large and exceeds the mean binding site volume of proteins,62 which is confirmed by comparing X-ray structures of fatty acid binding sites with random binding sites from PDBBind (Figure 1A). In any case, fatty acid binding sites

Figure 2. Distribution of calculated log S, molecular weight, calculated log P, number of hydrogen bond acceptors, and number of hydrogen bond donors in data sets derived from ChemblDB. Red: random ChemblDB compounds, green: approved drugs, blue: approved fatty acid mimetics; purple: fatty acid mimetics. A detailed interpretation of the boxplot can be found in Figure S1.

Figure 1. Comparison of fatty acid binding sites with random binding sites from PDBBind. (A) Approximation of the binding site volume. (B) Number of hydrophobic contacts in the receptor. Red: random binding sites accommodating ligands from PDBBind; purple: binding sites accommodating fatty acid mimetics. Detailed calculation methods are listed in the Supporting Information. Detailed interpretation of the boxplot can be found in Figure S1.

Not surprisingly, the mean calculated solubility coefficient, calculated as log S, of fatty acid mimetics is lower than the mean log S of drugs and random ChemblDB compounds. However, the mean log S of approved fatty acid mimetics significantly exceeds the mean log S of the entire fatty acid mimetics data set. This observation also holds true for the molecular weight. Although fatty acid mimetics seem to be considerably larger than average drugs or random ChemblDB compounds, the molecular weight of the approved subset is clearly in the range of all approved drugs. In contrast, significant differences occur in the average number of hydrogen bond donors and acceptors. Fatty acid mimetics, including approved representatives, display fewer functional groups containing hydrogen bond acceptors and donors, reflecting the hydrophobic nature of their binding sites.

exhibit more hydrophobic contacts (Figure 1B). Several membrane-associated fatty acid targets (e.g., FFARs, MAPEGs) comprise a binding site that is open toward the lipophilic environment of the membrane, which seems important for the entry of the ligands or substrates from the membrane. All these characteristics influence the structural shape of fatty acid mimetics. For their basic features to be examined, a data set composed of ligands annotated in ChemblDB63 was analyzed. The collection comprised 22,720 fatty acid mimetics binding to targets described in the introduction with an IC50, 5242



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3.2. Thermodynamics, Binding, and Molecular Recognition. As a consequence of the large and hydrophobic binding site of targets accommodating fatty acid derivatives, ligand binding is mediated to a considerable extent via nonpolar surface area forming van der Waals interactions. Therefore, the interactions of fatty acid mimetics with the corresponding binding sites might be expected to be mostly of entropic nature. However, thermodynamic characterization of fatty acid mimetics using the most popular technique, isothermal titration calorimetry (ITC),64 indicates that enthalpy-driven binding can be achieved by optimal filling of such hydrophobic binding sites. A recent study compared five ligands of LTA4H accommodating distinct regions of the binding site.65 Notably, LTA4H possesses two enzymatic activities: epoxide hydrolase activity catalyzing the conversion of LTA4 to LTB4 and aminopeptidase activity for degradation of the pro-inflammatory tripeptide Pro-Gly-Pro (PGP).66 Accordingly, the binding site of LTA4H is divided into two areas: a hydrophobic cleft accommodating the fatty acid derivative LTA4 and a hydrophilic subpocket recognizing PGP. The study revealed that only ligands interacting with the hydrophobic subpocket exhibit enthalpy-driven binding and that the enthalpic contribution to binding free energy does not necessarily depend on the number of hydrogen bonds (Figure 3). Similar data were obtained by examining the thermodynamics of fatty acid and fatty acid mimetic binding to intestinal fatty acid binding protein (I-FABP). Although I-FABP is not

considered a drug target itself, it significantly contributes to pharmacokinetic properties of lipophilic drugs.68 Fluorimetric binding affinity determination of van’t Hoff enthalpies of palmitic acid, fenofibric acid, clofibric acid, and tolfenamic acid69 revealed that binding of these compounds is explicitly driven by enthalpy. The authors state that the favorable entropic contribution to binding free energy “from the hydrophobic effect and displacement of ordered cavity waters is canceled by the decrease in conformational entropy of the ligand and protein upon complexation” (Table 4). Accordingly, Table 4. Processes Related to the Thermodynamics of Fatty Acid Mimetics (Adopted from ref 69) enthalpic factors Favorable ionic and hydrogen bonding interactions between protein and carboxylate (or carboxylate bioisostere) van der Waals interactions between hydrophobic cavity side chains and the hydrophobic tail component of the fatty acid mimetic increased hydrogen bonding across the protein backbone as result of tightened structure upon fatty acid mimetic binding hydrogen bonding between remaining structural waters within the cavity and the fatty acid mimetic Opposing loss of hydrogen bonds between ordered cavity waters and cavity side chains upon desolvation of the cavity with ligand entry entropic factors Favorable hydrophobic effect from the burial of hydrocarbon surface from exposure to water and loss of the hydration shell surrounding the hydrophobic molecule into the bulk solvent expulsion of ordered water molecules from the binding cavity into the bulk solvent upon ligand binding Opposing loss of rotational and translational degrees of freedom in both the protein and ligand upon complexation loss of degrees of freedom available to cavity waters when ligand is bound

calculations on the stability of water interactions in the hydrophobic subpocket of LTA4H indicate that water molecules displaced by fatty acid mimetics are not wellstabilized by hydrogen bonding. Thus, the loss of hydrogen bonding between water in the hydrophobic part of the binding site can be neglected and does not oppose other enthalpic contributions to binding free energy (Table 4). Crystal structures of I-FABP (PDB IDS: apo-state, 1IFB;71 holo-complex with palmitate, 2IFB;72 Figure 4) illustrate the stability of water interactions in a lipophilic binding site. The solvent distribution density in the holo structure calculated by the 3D-RISM method70 is in strong contrast to water molecules (green spheres) in the apo structure, suggesting that palmitate binding displaces these destabilized water molecules. Hence, solvent displacement by palmitate does not significantly disfavor enthalpy of binding, which is in congruence with the experimentally determined van’t Hoff thermodynamic parameters for the palmitate-I-FABP complex (ΔG° = 10 kcal/mol; ΔH° = −9 kcal/mol; TΔS° = 1.2 kcal/mol). Enthalpy-driven binding can be observed across a wide range of fatty acid mimetics and seems to be universal for a multitude of compound classes. There are numerous examples such as various PPARγ agonists73,74 and diverse cPLA2α ligands75 with extraordinary lipophilicity exhibiting almost entirely enthalpydriven binding. Furthermore, enthalpy-driven binding seems independent of the carboxylic moiety because binding of

Figure 3. Superposition of X-ray structures of LTA4 hydrolase in complex with captopril (1, red) and ARM1 (2, green).67 The molecular surface of the binding site is colored by lipophilicity (green: lipophilic; purple: hydrophilic). Thermodynamic data of ligand binding of 1 and 2 to LTA4 hydrolase measured by isothermal calorimetry. Binding of 1, which interacts with the hydrophilic catalytic center of LTA4H via ionic interactions, metal interactions, and hydrogen bonds, is balanced considering enthalpic and entropic contributions. In contrast, 2 binds to the hydrophobic subpocket and displays enthalpy-driven binding. 5243



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have been extensively reviewed.80 In this perspective, we focus on the most promising strategies enabling hit identification with respect to fatty acid mimetics. 3.3.1. Natural Compound Analogues and Mimetics. A most intuitive way to develop fatty acid mimetics is the use of the endogenous ligand as a template. Exhaustively reviewing fatty acid analogues is beyond the scope of this perspective, but some selected successful examples that reached clinical trials or approval shall be discussed. The prostaglandin analogue misoprostol (6, Scheme 1), used for ulcer prevention, labor induction, abortion, and treatment of postpartum bleeding, is a prime example of successfully optimizing an endogenous ligand to a potent fatty acid mimetic and is even found on the World Health Organization’s List of Essential Medicines. The antiulcerogenic and gastric antisecretory activities of PGE1 (3) and PGE2 (4) have been known for decades,81 but prostaglandins are rapidly metabolized by prostaglandin dehydrogenases through NAD+-mediated conversion of the C-15 hydroxyl moiety to a ketone,82 and therefore, more metabolically stable analogues were sought. The C-15 oxidation could be suppressed by a methyl group in said position,83 leading to the development of abraprostil (5).84 Unfortunately, abraprostil (5) and similar C-15-hydroxy PGE2 analogues caused pronounced side effects such as diarrhea and emesis.85 The side effects could subsequently be reduced by transposition of the hydroxyl moiety from C-15 to C-16.86 A methyl group at the carbon bearing the hydroxylic moiety and additional esterification of the carboxyl group for improved oral bioavailability generated the PGE1 analogue misoprostol (6). Another optimization of an endogenous ligand was realized in the development of prostaglandin F2α (7) derivatives for reducing intraocular pressure in the treatment of glaucoma and ocular hypertension. The optimization focused on improved ophthalmic bioavailability leading to the development of latanoprost (8)87 as a lipophilic ester prodrug with improved ocular delivery and reduced adverse effects on the eye surface.88 Additionally, by introduction of the phenyl ring into the omega chain, therapeutic selectivity in the eye was increased.89 At the site of action, latanoprost (8) was converted to its active metabolite latanoprost acid by esterases.90,91 The development of FXR agonists from the most potent endogenous bile acid CDCA predominantly tended to increase

Figure 4. Superposition of X-ray structures of I-FABP in complex with palmitate and in the apo-state. Colored spheres represent water molecules in the binding site (green: apo; red: holo with palmitate). Blue mesh indicates solvent distribution density in the apo structure calculated by the 3D-RISM70 method. The molecular surface of the binding site is colored by lipophilicity (green: lipophilic; purple: hydrophilic). The superposition reveals that the hydrophobic pocket contains water molecules that are not stabilized by interactions with the protein. Therefore, displacement of these water molecules by a ligand results in enthalpy-driven binding.

psoralidin to FLAP is mainly enthalpic whereas the entropic factors disfavor the binding event (Kd = 21 μM; ΔH° = −18.5 kcal/mol; ΔS° = 26.5 cal/mol).76 It is well precedented in medicinal chemistry that occupation of hydrophobic binding sites is highly favorable for a ligand’s binding potency.77 However, the underlying effects are diverse, and a global interpretation of effects contributing to binding is not unambiguous. In the case of fatty acid mimetics, occupation of hydrophobic binding sites seems to generate binding that primarily results from enthalpic effects. Because tight enthalpydriven binding is a key prerequisite for high affinity78 and selectivity,79 the prevailing thermodynamic binding behavior of fatty acid mimetics is favorable. 3.3. Hit and Lead Identification. High-quality hit structures are key prerequisites for most drug discovery campaigns. Different strategies to identify hit compounds Scheme 1. Prostagandins and Prostaglandin Analogues

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Figure 5. Distribution of acidic and basic structures in data sets derived from ChemblDB; 69% of fatty acid mimetics contain at least one acidic moiety in contrast to the majority of approved drugs and random compounds. Basic centers are not common in fatty acid mimetics.

mimetic HTS with high probability of hit identification are available in the public domain. Asinex offers a screening compound set composed for identification of lipid GPCR ligands, and some specialized vendors (Cayman Chemicals, Enzo) offer small fatty acid or bioactive lipid screening libraries. Another problem of fatty acid mimetics in HTS is their handling because highly lipophilic and poorly soluble chemicals can be absorbed by the labware. Therefore, the use of specialized coated and low-binding material is imperative for handling fatty acid mimetics in biological assays if acoustic dispensing systems are unavailable. Additionally, chemicals such as estrogenic impurities94 leaching from laboratory plasticware, including pipet tips, polystyrene plates, and microfuge tubes, can significantly influence biological assay systems.95 Finally, the occurrence of false positives caused by aggregation impedes HTS for fatty acid mimetics.96 Because of their amphiphilic nature, fatty acid mimetics tend to aggregate as has been demonstrated for mPGES-1,97 which is avoidable by the use of detergents in test systems.98 3.3.3. Virtual Screening. Virtual screening has become an important technology for hit identification in drug discovery99,100 and was the source of many novel scaffolds for lead optimization in the field of fatty acid mimetics. For PPARs in particular, many novel agonists are derived from virtual screening campaigns101 based on various techniques, including pharmacophore screening,102 shape-based screening,103 probabilistic networks,104 and molecular docking.105 It is remarkable that particular techniques based on shape superposition or shape complementarity dominate the virtual screening of fatty acid mimetics. A shape-based database search combined with molecular docking and analogue search,106 a combination of 3D shape, pharmacophore screening, and electrostatic similarity search,107 and surface-based shape overlay linked with fuzzy pharmacophore matching103 were equally successful in identifying novel PPAR ligands. General assessments revealed that shape-based virtual screening techniques such as the software Shapelets108 and rapid overlay of chemical structures (ROCS)109 perform particularly well on targets of fatty acid mimetics including COX-2,108 PPARγ, and RXRα.110 Fur-

potency and efficacy. CDCA activates FXR with an EC50 value of around 9 μM, which could robustly be enhanced by introducing aliphatic moieties in the 6α position of the steroid scaffold. A 6α-methyl group generated a 10-fold potency increase, which could be further boosted by an additional carbon in 6α-ethyl-CDCA (obeticholic acid (OCA)) that activates FXR with an EC50 value of 0.1 μM. OCA is currently in clinical trials for nonalcoholic steatohepatitis (NASH) and has recently gained approval by the FDA for primary sclerosing cholangitis (PBC).92 Although synthetic accessibility of the natural scaffolds may be a limitation, fatty acid mimetic development starting from endogenous ligands is a highly promising strategy. For success, the bioavailability and stability of the endogenous ligand have to be increased in most cases by protecting labile moieties from degrading enzymes. The need for potency and selectivity optimization depend on the endogenous template and its targets and must be evaluated carefully. 3.3.2. High-Throughput Screening (HTS). HTS is certainly among the most important sources for hit identification in drug discovery,93 including fatty acid mimetics. However, the success of an HTS campaign depends on the quality and suitability of its screening compound collection for the target of interest. In this context, it is interesting to examine the functional groups in potent fatty acid mimetics (Figure 5). Not surprisingly, the majority of fatty acid mimetics (68%) contain an acidic functionality, whereas only 5% of fatty acid mimetics display a basic moiety. These values are in strong contrast to approved drugs and random ChemblDB compounds where an acidic functionality is found in only 13 and 9%, respectively. Furthermore, the occurrence of basic molecules is significantly higher, especially among approved drugs. However, the acidic residue is a key pharmacophore feature for many fatty acid mimetic targets, and the introduction of basic moieties often prevents the compounds from binding. Naturally, the probability of hit identification in an HTS campaign in a standard compound library is lower if the library is designed to mimic average drugs. To our knowledge, only two focused libraries for discovery of fatty acid mimetics to enable fatty acid 5245



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privileged scaffolds for the design of fatty acid mimetics have not been examined so far. A very common substructure of many fatty acid mimetics reaching clinical trials or clinical use is indole (Scheme 2).

thermore, prospective virtual screening studies confirmed the success of shape based approaches for mPGES-1 inhibitors,111,112 5-lipoxygenase inhibitors,113 FXR agonists,114,115 and LXR agonists.116 Hence, in virtual screening of fatty acid mimetics, shape complementarity seems to be of particular importance for molecular recognition of fatty acid mimetics inside the buried hydrophobic binding sites of their targets. 3.3.4. Fragment-Based Design. In the last two decades, fragment-based design has became the fourth-most popular technique for lead identification and optimization in drug discovery.117 Several fragment-based development campaigns were also successfully applied to targets of fatty acid mimetics yielding, among others, the pan-PPAR agonist indeglitazar (10).118 Careful analysis of the successful studies provides hints for the setup of effective fragment-based screening for fatty acid mimetics. Accurate design of the fragment library is a key prerequisite for fragment-based design. Initially, fragments were defined by a rule-of-3 (MW < 300 Da, log P ≤ 3, number of hydrogen bond donors ≤ 3, and number of hydrogen bond acceptors ≤ 3)119 whereas later, a MW of 120−250 Da120 and MW < 230 Da121 were suggested as optimal for fragments. The library was successful in the discovery of indeglitazar-containing compounds with MW of 150−350 Da and very diverse scaffolds.122 The original hit 3-(5-methoxy-1H-indol-3-yl)propanoic acid initiating indeglitazar (10) discovery possessed a molecular weight of only 219 Da. A library called “fragments of life” (FOL) containing compounds with MW < 350 Da was screened for LTA4H inhibition, yielding hits that could successfully be optimized, and notably, no hit in this study exceeded a MW of 230 Da.123 Furthermore, two fragmentbased development campaigns to identify novel sEH inhibitors yielded hits with MW up to 270 Da, but all compounds exhibiting reasonable ligand efficiency were below 250 Da.124,125 PGDS inhibitors were even discovered by an NMR-based fragment screening126 of a focused library with compounds exhibiting MW < 200 Da and clogP < 2. These findings support the conclusion that, although targets for fatty acid mimetics comprise large hydrophobic binding pockets and fatty acid mimetics tend to have high molecular weight (vide supra), a commonly accepted cutoff for MW of 230−250 Da in fragment libraries delivers hits with very good ligand efficiencies. A valuable characteristic of fragment-based drug discovery of fatty acid mimetics is the option to start from a fragment representing the acidic headgroup. Such an approach yielded novel mPGES-1 inhibitors with catechol127 or 1,2,3-triazole-4,5dicarboxylic acid128 as starting points. Additionally, this strategy also worked for de novo design where a novel acidic headgroup was transferred to a common hydrophobic moiety yielding potent dual PPARα/γ agonists.129 Thus, fragment-based design represents a promising strategy for fatty acid mimetic development, but focused libraries of acidic fragments are missing. 3.4. Privileged Scaffolds of Fatty Acid Mimetics. Privileged scaffolds are a commonly used concept in drug discovery first introduced by Evans et al.,130 where a privileged scaffold is defined as a molecular framework providing a structural basis for ligands for multiple targets.131,132 Although privileged scaffolds across protein families have been discussed to provide promiscuous binders,133 family-specific privileged scaffolds, e.g., for kinases or GPCRs, can be useful for targeted libraries and rational drug design.134 To our knowledge,

Scheme 2. Four Indole-Based Fatty Acid Mimetics Active on Four Distinct Molecular Fatty Acid Targets that have Reached Clinical Trials or Clinical Use, which Highlights the Indole as a Privileged Scaffold of Fatty Acid Mimetics

Indomethacin (9), a nonselective COX inhibitor widely used for the treatment of inflammatory conditions,135 indeglitazar (10), a pan-PPAR agonist discovered by fragment-based design that reached clinical trials for type 2 diabetes mellitus,118 the FLAP inhibitor fiboflapon (11) currently under clinical investigation for asthma,136 and the CysLT antagonist zafirlukast (12c) approved for the same indication137 are all built up from an indole moiety. Indoles are well-described as privileged scaffolds in general,138 and it has been discussed that target-family privileged substructures are common for all target families, which holds true for the indole.139 However, indomethacin (9) and zafirlukast (12c) display pronounced polypharmacological behavior among fatty acid accommodating targets with indomethacin activating PPARα and PPARγ140 and inhibiting the leukotriene B4 12-hydroxydehydrogenase/15oxo-prostaglandin 13-reductase complex141 and zafirlukast (12c) inhibiting mPGES-1.142 These observations strongly support the conclusion that indole is a prime example for a privileged scaffold in fatty acid mimetics. 2-([4-Chloro-6-{(2,3-dimethylphenyl)amino}pyrimidin-2yl]thio)acetic acid (pirinixic acid, WY14643143), originally discovered as a cholesterol lowering agent, was excessively used as a scaffold for fatty acid mimetics with a wide range of targets.144 Several derivatives of the compound were optimized as selective PPAR modulators,145 preferential dual PPARα/γ agonist,146 or as dual 5-LO/mPGES-1 inhibitors,147 exhibiting excellent in vivo activity.148 On the basis of their highly variable and tractable structures, their selectivity profiles can be specifically directed toward different targets, which qualifies their core structure, namely, a 2,4-disubstituted pyrimidine system as a privileged scaffold of fatty acid mimetics. Further analysis of privileged scaffolds among fatty acid mimetics was performed in the fatty acid mimetics data set collected from ChemblDB (vide supra) from which 588 unique scaffolds were extracted using the Murcko Scaffold node (provided by EPAM Systems, Inc. and the Indigo Toolkit) in KNIME. Subsequently, unique targets were counted for each 5246



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Scheme 3. Privileged Scaffolds with the Number of Unique Targets of Fatty Acid Mimetics Derived from ChemblDB with the Number of Unique Compounds Given in Parentheses

Scheme 4. Properties of Carboxylate Bioisosteres in CysLT1 Antagonists

carboxylate and another 10% comprise an ester moiety that is rapidly degraded to a carboxylate in vivo. Still, it is reasonable to replace the carboxylate by a bioisosteric moiety in some cases. Carboxylates poorly penetrate the blood-brain barrier151 and can cause idiosyncratic toxicities resulting from their metabolism (see section 4.3.2). Bioisosteres in general152 and bioisosteres of carboxylic acids in particular150 have been extensively reviewed and analyzed for their structure−property relationships.153 Hence, this perspective shall only focus on bioisosteres successfully employed in approved drugs and their properties compared to those of carboxylates. The most prominent fatty acid mimetics carrying a carboxylate bioisoster are thiazolidinediones (glitazones), which are selective full agonists of PPARγ acting as insulin sensitizers for the treatment of type 2 diabetes mellitus.154 Interestingly, the bioisosteric thiazolidinedione moiety in this case ensures selectivity against other PPAR subtypes because the heterocycle is bulkier than a carboxylate moiety and can

scaffold. Scheme 3 summarizes all privileged fatty acid mimetic scaffolds identified from the data set that matched at least five fatty acid mimetic targets. Most of the scaffolds contain interconnected phenyl rings, whereas nitrogen-containing heterocycles are a minority. Strikingly, the majority of linkers comprise ether residues, whereas amines, amides, sulfonamides, and ureas are rare. Obviously, phenyl moieties linked via ethers are well-suited for occupying hydrophobic areas in targets accommodating fatty acid mimetics. Of note, biphenyl and the diphenylmethane moieties are considered as general privileged scaffolds for protein binding.149 3.5. Bioisosteres of Carboxylic Acids. As discussed above, the acidic headgroup is an essential pharmacophore element of fatty acid mimetics. Furthermore, the carboxylic acid moiety is highly druglike with more than 450 marketed drugs for various indications containing this functional group150 and a privileged functional group for protein binding.149 In the approved fatty acid mimetics data set, 63% contain a 5247



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considerable obstacles to the desired activity of a drug, especially for CNS-active compounds. For such cases, nonacidic fatty acid mimetics are required, and several data demonstrate that it is possible to develop fatty acid mimetics without the classical acidic head (Scheme 6). A nonacidic benzimidazole hit structure identified in HTS, for example, was optimized to a potent PPARγ agonistic and brain-penetrant lead GSK1997132B (18).161 Comparison of PPARγ cocrystal structures in complex with 18 and rosiglitazone,162 respectively, indicate a pronounced adaptation of the amino acid residues interacting with the carboxylate function (Figure 6). In the

selectively interact with four amino acids required for PPARγ activation. In PPARα and PPARδ, H323 of PPARγ is replaced by a more sterically demanding tyrosine, which is why these subtypes cannot accommodate a thiazolidinedione. The development of CysLT antagonists has resulted in further interesting applications of carboxylic acid bioisosteres (Scheme 4). The N-acylsulfonamide zafirlukast (12c) was developed from the so-called inverted indole series of which the carboxylate derivative 12a exhibits a Ki against [3H]LTD4 of 157 nM, whereasile the N-acylsulfonamides 12b and 12c (zafirlukast) are more potent by 2 orders of magnitude.137 Similarly, in the development of pranlukast (13),155 bioisosteric replacement of a carboxylic acid in lead structure 14a by a tetrazole in 14b enhanced the potency by a factor 8. As illustrated by these examples, bioisosteric replacement of the carboxylic group can be used to optimize potency and selectivity of fatty acid mimetics. Notably, there are also some approved drugs that are active on fatty acid mimetic targets whose carboxylic acid bioisosteres do not mimic the carboxylate but fulfill a different purpose (Scheme 5). One such example is the only approved 5-LO Scheme 5. Fatty Acid Mimetics with Carboxylate Bioisosteres Not Resembling the Carboxylate of the Endogenous Ligand

Figure 6. Superposition of PPARγ agonists 18 (PDB ID: 3S9S; red carbons) and rosiglitazone (PDB ID: 4EMA; green carbons). Rosiglitazone forms hydrogen bonds to all four residues responsible for PPARγ activation, whereas in the complex of 18 with PPARγ, H323 and H449 are shifted to enable intramolecular hydrogen bonding toward Y473.

acidic thiazolidindione binding mode, all four residues, S289, H323, Y473, and H449, form hydrogen bonds with the ligand. In contrast, in the complex of 18, only S289 and H323 participate in ligand binding, whereas Y473 and H449 form intramolecular hydrogen bonds. Another example for the successful development of a nonacidic fatty acid mimetic is the FLAP inhibitor AZD6642 (19),163 which displays excellent potency, a favorable log P value of 1.7, and a bioavailability of 100% in dogs. Nonacidic fatty acid mimetics are most commonly identified by HTS because their rational design, e.g., from endogenous compounds, is difficult. To our knowledge, there are no nonacidic fatty acid mimetics approved as drugs. However, some approved nonacidic drugs, which were designed to

inhibitor zileuton (15) with a hydroxyurea residue, which can be considered as a carboxylate bioisostere complexing the Fe3+ ion in the catalytic center of 5-LO.156 In this position, the C-5 carbon, and not the carboxylic acid moiety of the arachidonic acid, is located for catalysis of hydroperoxidation.157,158 Similarly, in selective COX-2 inhibitors, such as celecoxib (16) and valdecoxib (17),159 the positioning of the bioisosteric sulfonamide does not resemble the location of the carboxylate moiety of the arachidonic acid substrate.160 3.6. Nonacidic Compounds. As mentioned above, carboxylic acid or similar acidic moieties sometimes constitute Scheme 6. Examples of Nonacidic Fatty Acid Mimetics

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Opposite to selectivity, polypharmacology can also be systematically designed with licofelone (21, Scheme 7), for

interact with nonfatty acid targets, modulate targets of fatty acid mimetics at therapeutically relevant concentrations, such as sorafenib (20) potently inhibiting sEH.164 Although the pharmacological relevance of this activity is not unambiguously clear yet, it illustrates that nonacidic fatty acid mimetics are developable and that, eventually, approved drugs are valuable leads for approaches of selective optimization of side activities (SOSA).165 With rising interest in targeting nuclear receptors such as PPARs or RXRs in the CNS in particular,7,166 brainpenetrating nonacidic fatty acid mimetics might have high therapeutic potential. 3.7. Selectivity vs Polypharmacology of Fatty Acid Mimetics. The past decade has seen the controversially discussed onset of a paradigm change in drug discovery toward the development of polypharmacologically active compounds instead of selective ligands.167 Polypharmacology and polypharmacologically active compounds in the field of fatty acid mimetics, with a special focus on anti-inflammatory compounds, have extensively been reviewed.25,26,168 This perspective shall focus on structural options of designing either selectivity against related targets or polypharmacological behavior. A repeatedly successful strategy of designing selective fatty acid mimetics is the introduction of a specific acidic headgroup ensuring selectivity with the selectively PPARγ agonistic thiazolidinediones as the most prominent example. Similar strategies were successful for various scaffolds on distinct targets. Anthranilic acid derivatives could be rendered highly selective and potent FXR partial agonists by using 3-aminobenzoic acid as headgroup,169 whereas a 3-amino-phenylacetic acid moiety shifted activity toward PPARδ agonism.5 Similar effects of the acidic headgroup were observed for selective FFAR1 agonists, where selectivity against FFAR4 was achieved by introduction of a 2-fluoro-phenylpropionic acid moiety.170 Alternatively, selectivity can be generated by methylation in positions with slight differences in the size of interacting amino acid residues. Here, lumiracoxib is a prime example, where a single methyl group was employed to introduce COX-2 selectivity into the unselective COX inhibitor diclofenac.171 Similar effects of single methyl groups in specific positions modulated PPAR subtype selectivity of anthranilic acid derivatives.5 Instead of additional methyl groups, the exploitation of additional H-bond donor or acceptor residues for further interactions with the target or a complexed water molecule146 proved successful in generating selectivity. Celecoxib (13) is an example where introduction of a sulfonamide moiety enhanced the selectivity.172 Likewise, the introduction of an amide moiety in the linker region of a series of pan-PPAR agonists caused PPARα selectivity.173 Hydrogen bonding interactions to water molecules in the binding site can even serve as a uniform strategy for optimizing binding affinity and selectivity and for reducing the lipophilicity of fatty acid mimetics. The potent dual PPARα/γ agonist 2-((4-chloro-6-((4-(phenylamino)phenyl)amino)pyrimidin-2-yl)thio)octanoic acid146 forms interactions with a conserved water cluster in the PPARα binding site via its backbone diphenylamino moiety as shown by molecular docking, structure−activity relationship studies, and site-directed mutagenesis disturbing the water cluster. This water-mediated interaction seems to significantly improve the compound’s potency on PPARα, and the presence of an amine moiety tolerated by the target enhances its solubility.

Scheme 7. Examples of Multitarget Fatty Acid Mimetics

example,174 which was originally designed as a dual 5-LO/COX inhibitor but also inhibits the formation of leukotrienes and prostaglandins via interaction with mPGES-1175 and FLAP.176 By the so-called design-in strategy,177 a potent COX but weak LO inhibitor was turned into a balanced compound by systematic variation of the substitution pattern. Furthermore, this strategy was successfully employed to identify dual sEH/ PPARγ modulators such as 22, where balanced dual activity was highly dependent on the substitution pattern on the benzylamide moiety.178 Suitable scaffolds for polypharmacological compounds can be identified in either biochemical118 or virtual179,180 fragment-based screening. Although linking of two pharmacophores can also deliver highly potent compounds in the field of fatty acid mimetics, it may result in large insoluble compounds with limited applicability in vivo.181 Therefore, it seems more advisible to start with a small ligand exhibiting moderate or even weak activity toward both targets of interest and simultaneously optimize its potency.

4. PROPERTIES, DRUG-LIKENESS, AND PHARMACOKINETICS Fatty acid mimetics put high demands on a medicinal chemist concerning their druglike properties, bioavailability, and pharmacokinetics. In a globally simplified view, fatty acid mimetics for the purpose of resembling the shape of fatty acids and to be recognized by fatty acid binding proteins comprise two main structural elements. These moieties correspond to the natural structure of fatty acid metabolites and constitute an acidic headgroup mimicking the carboxylic acid residue of fatty acids as well as a lipophilic tail that may significantly vary in its shape and geometry but rarely contains polar residues in the natural template. A major challenge in the development of fatty acid mimetics is, therefore, combining the desired pharmacodynamic activity with favorable or at least acceptable properties concerning solubility, bioavailability, and pharmacokinetics. Acidic compounds in general and carboxylic acids in particular follow their own rules in absorption, distribution, membrane interaction, metabolism, and elimination. Thereby, the acidic moiety is sometimes beneficial and sometimes complicates successful drug discovery. Nevertheless, the presence of a carboxylic acid or a respective bioisoster in more than one-fourth of marketed drugs allows the prediction and prevention of some liabilities associated with this highly prevalent moiety in medicinal chemistry. The additional presence of a highly hydrophobic tail with a most unusual high number of sp3 centers and rotatable bonds, however, adds up to the entire challenge of fatty acid mimetic design. 5249



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4.1. Physicochemical Properties, Solubility, and DrugLikeness. An obvious issue of fatty acid mimetics as potential drugs and drug candidates is their usually poor solubility. Owing to the lipophilic nature of binding pockets in fatty acid binding proteins and the lipophilic structure of fatty acids, it is a major challenge to insert polar residues in fatty acid-mimicking molecules except for the common acidic function. The acidic head of fatty acid mimetics already delivers a considerable amount of polarity to the molecules, especially in the ionized state. Carboxylic acids are significantly more soluble in ionized form, which prevails at physiologic pH. For improving solubility, absorption, and bioavailability, acidic compounds can be converted to their respective sodium, potassium, or ammonium salts, which comprise significantly better solubility. Additionally, significant improvement of poor solubility can be achieved by introduction of a basic center rendering the resulting molecule a zwitterion. Approximately one-third of approved drugs containing a carboxylic acid moiety also comprise a basic residue, but according to section 3.3.2, this does not hold true for fatty acid mimetics. In contrast, only approximately 10% of generic compounds with a carboxylic acid group are zwitterions, suggesting the potential value of a zwitterionic structure for the drug properties. Further comparison of marketed drugs with or without acidic moieties revealed little differences concerning molecular weight, H-bond donor and acceptor count, and clogP value, which for most drugs stick to Lipinski’s rule of 5 or even below (Table 5).

ester prodrug formation, the stability of the ester and its degree of lipophilicity can be controlled. Modern prodrugs of carboxylic acids also contain self-immolative prodrugs comprising a cleavable ester function connected to a linker that cleaves spontaneously after hydrolysis of the ester. This strategy has successfully improved the bioavailability of ampicillin in bacampicillin and pivampicillin. However, in fatty acid mimetics, the use of ester prodrugs is rarely required because the compounds usually possess sufficient lipophilicity to allow permeability.187 Many of the natural templates of fatty acid mimetics contain a high fraction of sp3 carbon atoms and a high degree of saturation, which might translate to a high count of sp3 atoms in fatty acid mimetics with beneficial and negative effects. Molecules with a large fraction of sp3 centers and higher degree of saturation were found to display better solubility and lower melting points, which both enhance bioavailability and drug performance in vivo. On the other hand, the planarity of compounds is reduced with increasing number of sp3 carbon atoms, which reduces permeability through lipid membranes and therefore has negative effects on bioavailability as well. And finally, a high number of sp3 carbon atoms also boosts the number of potential asymmetric centers. A higher degree of complexity as measured by the amount of stereogenic centers through impeding synthesis and purification is associated with higher selectivity and lower promiscuity.184,189 4.2. Pharmacokinetics. As a consequence of their special molecular framework of an acidic head and lipophilic scaffold, fatty acid mimetics follow some specific pharmacokinetic pathways that significantly affect their overall pharmacokinetic profile. After absorption, which is mainly mediated by passive permeation in the small intestine, fatty acid mimetics are transported in blood strongly bound to serum albumin. Clearance of fatty acid mimetics is significantly affected by specific uptake into hepatocytes by organic anion transporters and subsequent hepatic metabolic conversion, which is dominated by secondary metabolism, i.e., conjugation. 4.2.1. Bioavailability. Sufficient oral bioavailability is a highly important though challenging drug attribute that depends on a wide variety of factors. Total bioavailability results from a compound fraction that is absorbed, a fraction that is not promptly eliminated in the intestinal wall, and a fraction that undergoes hepatic clearance in the first pass. Each of these measures is affected differently by structural properties of a drug, and therefore, bioavailability follows specific rules for fatty acid mimetics.192 Most orally bioavailable drugs are absorbed in the small intestine, which displays a pH value of 6−8. In this range, carboxylic acids and similarly acidic bioisosteres prevail in the deprotonated state to a considerable extent and are negatively charged, which enhances their solubility in the small intestine but negatively affects their permeability. The passive permeability of fatty acid mimetics through lipid membranes in the small intestine is affected by two factors. First, lipid membranes comprise negatively charged residues facing the surrounding solvent and reject the negative charge present in acidic compounds at neutral pH of the small intestine. Second, membrane permeability generally increases with lipophilicity, and therefore, any charge hinders the permeation, rendering acidic compounds frequently poorly permeable. Acids with a pKa value below 3 are almost completely ionized at intestinal pH values and therefore fail in passive permeation. With increasing pKa value, the degree of ionization decreases,

Table 5. Empiric Druglike Properties for Acidic Drugs/Fatty Acid Mimetics190,191

molecular weight H-bond donors H-bond acceptors rotatable bonds log P log D7.4 TPSA pKa

general (classical rule of 5)

acidic drugs/fatty acid mimetics

10,000 against barium chloride).241 Simultaneous optimization of the indole backbone led to numerous equipotent analogues (40a− c) with indazole derivative 40c as the most potent.242 Compound 40c proved to be selective over a variety of related G-protein-coupled receptors including α-1/2, β-1/2, histamine H1,2, muscarinic, thromboxane, and prostaglandin receptors in ex vivo experiments.242 Poor oral bioavailability of less than 1% of 40c in dogs and rats was finally improved to more than 30% for 41 by application of an “inverted” indole, a classical privileged scaffold of fatty acid mimetics.137 In final SAR studies on the phenylsulfonamide residue, oral activity could be further enhanced by the introduction of ortho substituents such as a methyl group (12c) or a chlorine atom (42). Zafirlukast, the methyl derivative 12c, revealed the highest bioavailabilities of 68 and 67% for rats and dogs, respectively, and an IC50 value of 1.8−2.6 nM.223,227,228 Zafirlukast is also selective over CysLT2 (>3,800-fold)234 but weakly (EC50 = 30.6 μM) activates pregnane X receptor (PXR) causing CYP3A4 induction.243 Zafirlukast has gained approval in more than 60 countries, including the U.S. and Japan. 5.5. Summary. Although all approved selective CysLT1 receptor antagonists, montelukast, pranlukast, and zafirlukast, are derived from only two lead structures, the endogenous agonist LTD4 and the early antagonist 24, structure−activity relationship studies led to three different highly potent fatty acid mimetic drugs. All approaches were more closely related to

6. CONCLUSIONS AND FUTURE DIRECTIONS Although fatty acid mimetics address a wide range of molecular targets, they share many commonalities. Derived from their natural templates, i.e., various endogenous fatty acids and fatty acid metabolites, fatty acid mimetics comprise high structural similarity manifested in a lipophilic scaffold bearing an acidic headgroup. Consequently, the properties as well as the pharmacokinetic profile of fatty acid mimetics are alike and are mainly governed by the acidic moiety. Furthermore, the thermodynamic behavior, which is characterized by enthalpydriven binding mediated by the lipophilic scaffold, constitutes an important common feature of fatty acid mimetics. Finally, according to their significant structural resemblance, the design concept of fatty acid mimetics is similarly irrespective of the addressed target. Therefore, considering fatty acid mimetics as a class of drugs with their own rules seems justified. Beyond their role as a nutritional energy source and endogenous energy storage, fatty acids are increasingly considered as important signaling molecules that can cause numerous physiological and pathophysiological effects. Their molecular targets, ranging from enzymes over surface receptors to nuclear receptors, therefore, hold enormous pharmacological potential. As implied by the number of fatty acid mimetics successfully used as drugs, targets of fatty acids can be therapeutically exploited with clinical efficacy and are well druggable. The significant potential for fatty acid mimetics lies 5257



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Biographies

in the existence of several fatty acid targets that are not addressed by marketed drugs to date. Many of these receptors and enzymes hold considerable potential for the treatment of metabolic or inflammatory diseases and are gaining particular attention in drug discovery. Hit retrieval for the development of fatty acid mimetics is equivalent to general drug development and effective in standard methods. In HTS, it must be considered that suitable candidates usually constitute only a small fraction of the library. Therefore, significant progress might be possible with the establishment of focused libraries for fatty acid mimetics. Fatty acid mimetics can be considered as an advantageous compound class in principle. Their ionizable acidic moiety is valuable by promoting solubility at intestinal pH and comprising low clearance and limited toxicity. The lipophilic scaffold is essential for target binding of fatty acid mimetics that is usually dominated by enthalpic contributions. This thermodynamic behavior is very favorable, and therefore, high lipophilicity is not mandatorily disadvantageous in fatty acid mimetics. Hence, the challenge in designing fatty acid mimetics lies in generating a desirable pharmacokinetic profile. In this respect, the carboxylate has an ambivalent role by beneficial effects on solubility and detrimental impact on permeability. In the design, an appropriate balance of pKa, solubility, and permeability must be found. Beyond poor permeability, metabolism might be a challenge to fatty acid mimetics with fast modification of a free β-position or conjugate formation causing rapid clearance. Furthermore, glucuronides or intermediately formed CoA adducts constitute a nonspecific toxicity risk as they are highly reactive. This problem can be faced with bioisosteres of the carboxylate. Bioisosteres may sometimes also be beneficial for potency and selectivity but, overall, are rarely necessary for the development of a successful fatty acid mimetic. In a simplified view, fatty acid mimetics should be kept small (low MW) and comprise a moderate pKa value. Solubility, permeability, and nonspecific toxicity of metabolites should be considered and monitored early. With these measures in mind, fatty acid mimetic development is very promising. In conclusion, the opportunities for fatty acid mimetics concerning their therapeutic value widely outweigh the challenges they face in drug discovery.

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Ewgenij Proschak is a Junior-Professor for Drug Design at the Institute of Pharmaceutical Chemistry at the Goethe University of Frankfurt. After his doctoral and postdoctoral studies at Goethe University, he became Independent Group Leader at the Lipid Signaling Research Center (LIFF) in Frankfurt. Currently, the German Research Council (DFG) awarded him with a Heisenberg Fellowship. He has worked on hit identification and hit-to-lead optimization for fatty acid mimetics including inhibitors of 5-LO, mPGES-1, sEH, and LTA4H and modulators of PPARs and FXR. His current research interests are the design and synthesis of multitarget drugs for the treatment of inflammatory conditions and metabolic syndrome. Pascal Heitel studied Chemistry at Ulm University and the University of Málaga. After receiving his M.Sc. in 2015, he joined the group of Manfred Schubert-Zsilavecz at Goethe University of Frankfurt for graduate studies. He is a fellow of the Else-Kroener-Fresenius Foundation and a member of the graduate school “Translational Research Innovation−Pharma” (TRIP). The main focus of his research is the development and identification of novel nuclear receptor modulators with anti-inflammatory properties. Lena Kalinowsky received her M.Sc. in Chemistry from Goethe University in Frankfurt, Germany in 2015. Lena is currently working toward her Ph.D. at the Institute for Pharmaceutical Chemistry at Goethe University Frankfurt. Lena’s current work focuses on molecular modeling, structure-based drug design, and virtual screening. Daniel Merk graduated in Pharmacy and Pharmaceutical Sciences at the Ludwig-Maximilians-University Munich and received his Ph.D. in Pharmaceutical/Medicinal Chemistry from Goethe University Frankfurt. Since 3/2015, he is junior group leader at the Institute of Pharmaceutical Chemistry of Goethe University Frankfurt and since 3/2017 is an ETH-fellowship scholar at ETH Zürich. His research interests focus on the exploration of nuclear receptors as pharmaceutical targets and the medicinal chemistry of synthetic nuclear receptor modulators with special emphasis on FXR, PPARs, and RXRs.

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ACKNOWLEDGMENTS P.H. gratefully acknowledges financial support by the ElseKroener-Fresenius-Foundation, graduate school “Translational Research Innovation−Pharma” (TRIP). This research was supported by Deutsche Forschungsgemeinschaft (DFG; Sachbeihilfe PR 1405/2-2; Heisenberg-Professur PR 1405/41; SFB 1039 Teilprojekt A07) and by research funding programe Landes-Offensive zur Entwicklung Wissenschaftlichökonomischer Exzellenz (LOEWE) of the State of Hessen, Research Center for Translational Medicine and Pharmakology TMP). The authors thank Dr. Ilse Zündorf for assistance preparing the Table of Content graphic.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.6b01287.

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Experimental data for fatty acid mimetic binding site and molecular structure evaluation (PDF)

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AUTHOR INFORMATION

ABBREVIATIONS USED ADME: absorption, distribution, metabolism, and excretion; AFABP: adipocyte fatty acid binding protein 2; ALX: N-formyl peptide receptor; aP2: adipocyte protein 2; APL: acute promyelocytic leukemia; ApoE: apolipoprotein E; BLT: leukotriene B4 receptor; CDCA: chenodeoxycholic acid; ChemR: chemerin receptor; CMKLR: chemokine-like receptor; CNS: central nervous system; CoA: coenzyme A; COPD: chronic obstructive pulmonary disease; COX: cyclooxygenase; cPGES: cytosolic prostaglandin E synthase; cPLa: cytosolic phospholipase a; CRTh2: chemoattractant receptor expressed

Corresponding Authors

*Phone: +49 69 798 29301. E-mail: proschak@pharmchem. uni-frankfurt.de. *Phone: +49 69 798 29327. E-mail: [email protected]. ORCID

Ewgenij Proschak: 0000-0003-1961-1859 Notes

The authors declare no competing financial interest. 5258



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(3) Kersten, S.; Desvergne, B.; Wahli, W. Roles of PPARs in Health and Disease. Nature 2000, 405 (6785), 421−424. (4) Lamers, C.; Schubert-Zsilavecz, M.; Merk, D. Therapeutic Modulators of Peroxisome Proliferator-Activated Receptors (PPAR): A Patent Review (2008−present). Expert Opin. Ther. Pat. 2012, 22 (7), 803−841. (5) Merk, D.; Lamers, C.; Weber, J.; Flesch, D.; Gabler, M.; Proschak, E.; Schubert-Zsilavecz, M. Anthranilic Acid Derivatives as Nuclear Receptor modulatorsDevelopment of Novel PPAR Selective and Dual PPAR/FXR Ligands. Bioorg. Med. Chem. 2015, 23 (3), 499−514. (6) Ratziu, V.; Harrison, S. A.; Francque, S.; Bedossa, P.; Lehert, P.; Serfaty, L.; Romero-Gomez, M.; Boursier, J.; Abdelmalek, M.; Caldwell, S.; Drenth, J.; Anstee, Q. M.; Hum, D.; Hanf, R.; Roudot, A.; Megnien, S.; Staels, B.; Sanyal, A.; Mathurin, P.; Gournay, J.; Nguyen-Khac, E.; De Ledinghen, V.; Larrey, D.; Tran, A.; Bourliere, M.; Maynard-Muet, M.; Asselah, T.; Henrion, J.; Nevens, F.; Cassiman, D.; Geerts, A.; Moreno, C.; Beuers, U. H.; Galle, P. R.; Spengler, U.; Bugianesi, E.; Craxi, A.; Angelico, M.; Fargion, S.; Voiculescu, M.; Gheorghe, L.; Preotescu, L.; Caballeria, J.; Andrade, R. J.; Crespo, J.; Callera, J. L.; Ala, A.; Aithal, G.; Abouda, G.; Luketic, V.; Huang, M. A.; Gordon, S.; Pockros, P.; Poordad, F.; Shores, N.; Moehlen, M. W.; Bambha, K.; Clark, V.; Satapathy, S.; Parekh, S.; Reddy, R. K.; Sheikh, M. Y.; Szabo, G.; Vierling, J.; Foster, T.; Umpierrez, G.; Chang, C.; Box, T.; Gallegos-Orozco, J. Elafibranor, an Agonist of the Peroxisome Proliferator−Activated Receptor−α and − δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening. Gastroenterology 2016, 150 (5), 1147−1159. (7) Hanke, T.; Merk, D.; Steinhilber, D.; Geisslinger, G.; SchubertZsilavecz, M. Small Molecules with Anti-Inflammatory Properties in Clinical Development. Pharmacol. Ther. 2016, 157, 163−187. (8) Pollock, C. B.; Rodriguez, O.; Martin, P. L.; Albanese, C.; Li, X.; Kopelovich, L.; Glazer, R. I. Induction of Metastatic Gastric Cancer by Peroxisome Proliferator-Activated Receptorδ Activation. PPAR Res. 2010, 2010, 571783. (9) Altucci, L.; Leibowitz, M.; Ogilvie, K.; de Lera, A.; Gronemeyer, H. RAR and RXR Modulation in Cancer and Metabolic Disease. Nat. Rev. Drug Discovery 2007, 6 (10), 793−810. (10) Dawson, M.; Xia, Z. The Retinoid X Receptors and Their Ligands. Biochim. Biophys. Acta, Mol. Cell Biol. Lipids 2012, 1821 (1), 21−56. (11) Germain, P.; Chambon, P.; Eichele, G.; Evans, R. M.; Lazar, M. A.; Leid, M.; De Lera, A. R.; Lotan, R.; Mangelsdorf, D. J.; Gronemeyer, H. International Union of Pharmacology. LXIII. Retinoid X Receptors. Pharmacol. Rev. 2006, 58 (4), 760−772. (12) de Lera, Á . R.; Krezel, W.; Rühl, R. An Endogenous Mammalian Retinoid X Receptor Ligand, At Last! ChemMedChem 2016, 11 (10), 1027−1037. (13) Koster, K. P.; Smith, C.; Valencia-Olvera, A. C.; Thatcher, G. R. J.; Tai, L. M.; LaDu, M. J. Rexinoids as Therapeutics for Alzheimer Disease: Role of APOE. Curr. Top. Med. Chem. 2017, 17 (6), 708− 720. (14) Liby, K.; Sporn, M. Rexinoids for Prevention and Treatment of Cancer: Opportunities and Challenges. Curr. Top. Med. Chem. 2017, 17 (6), 721−730. (15) de Lera, A.; Bourguet, W.; Altucci, L.; Gronemeyer, H. Design of Selective Nuclear Receptor Modulators: RAR and RXR as a Case Study. Nat. Rev. Drug Discovery 2007, 6 (10), 811−820. (16) Germain, P.; Chambon, P.; Eichele, G.; Evans, R. M.; Lazar, M. A.; Leid, M.; De Lera, A. R.; Lotan, R.; Mangelsdorf, D. J.; Gronemeyer, H. International Union of Pharmacology. LX. Retinoic Acid Receptors. Pharmacol. Rev. 2006, 58 (4), 712−725. (17) Larange, A.; Cheroutre, H. Retinoic Acid and Retinoic Acid Receptors as Pleiotropic Modulators of the Immune System. Annu. Rev. Immunol. 2016, 34 (1), 369−394. (18) Kuipers, F.; Bloks, V. W.; Groen, A. K. Beyond Intestinal SoapBile Acids in Metabolic Control. Nat. Rev. Endocrinol. 2014, 10 (8), 488−498.

on Th2 cells; CYP: cytochrome P450; CysLT: cysteinyl leukotriene receptor; DHA: docosahexaenoic acid; DHET: dihydroxyeicosatrienoic acid; EET: epoxyeicosatrienoic acid; EMA: European Medicines Agency; EP: prostaglandin E2 receptor; EPA: eicosapentaenoic acid; FABP: fatty acid binding protein; FDA: Food and Drug Administration; FFAR: free fatty acid receptor; FLAP: 5-lipoxygenase-activating protein; FOL: Fragments of life; FP: N-formyl prostaglandin F receptor; FXR: farnesoid X receptor; GIP: gastric inhibitory polypeptide; GLP: glucagon-like peptide; GPCR: G-protein-coupled receptor; hERG: human ether-à-go-go-related gene; HETE: hydroxyeicosatetraenoic acid; HPETE: hydroperoxyeicosatetraenoic acid; H-PGDS: hematopoietic prostaglandin D synthase; HTS: highthroughput screening; I-FABP: intestinal fatty acid binding protein; IL: interleukin; IP: prostacyclin receptor; ITC: isothermal titration calorimetry; KNIME: Konstanz Information Miner; LCFAs: long chain fatty acids; LO: lipoxygenase; LOX: lipoxygenase; L-PGDS: lipocalin-type prostaglandin D synthase; LTA4: leukotriene A4; LTA4H: leukotriene A4 hydrolase; LTB4: leukotriene B4; LTC4: leukotriene C4; LTC4S: leukotriene C4 synthase; LTD4: leukotriene D4; LTE4: leukotriene E4; LXA4: lipoxin A4; LXR: liver X receptor; MAPEG: membrane-associated proteins in eicosanoid and glutathione metabolism; MCFAs: medium chain fatty acids; mPGES-1: microsomal prostaglandin E synthase 1; MRP: multidrug resistance proteins; NASH: nonalcoholic steatohepatitis; NR: nuclear receptor; NSAIDs: nonsteroidal anti-inflammatory drugs; NTCP: Na+-taurocholate cotransporting polypeptide; OAT: organic anion transporter; OATP: organic anion-transporting polypeptides; OCA: obeticholic acid; PBC: primary sclerosing cholangitis; PGD: prostaglandin D; PGDS: prostaglandin D synthase; PGE: prostaglandin E; PGF: prostaglandin F; PGFS: prostaglandin F synthase; PGG: prostaglandin G; PGH: prostaglandin H; PGI: prostaglandin I; PGIS: prostaglandin I synthase; PGP: pro-inflammatory tripeptide Pro-Gly-Pro; P-gp: P-glycoprotein; PPAR: peroxisome proliferator-activated receptor; PXR: pregnane X receptor; RAR: petinoic acid receptor; ROCS: papid overlay of chemical structures; RvD: pesolvin D; RvE: pesolvin E; RXR: petinoid X receptor; SAR: structure−activity relationship; SCD1: stearyl CoA desaturase 1; SCFAs: short chain fatty acids; she: Soluble epoxide hydrolase; siRNA: small interfering ribonucleic acid; SOSA: selective optimization of side activities; SPM: specialized proresolving mediators; SRS-A: slow-reacting substance of anaphylaxis; TGR5: Takeda G-protein receptor 5; TLR: Toll-like receptor; TNFα: tumor necrosis factor α; TP: thromboxane receptor; TPSA: topological polar surface area; TR: thyroid hormone receptor; TRPV1: transient receptor potential V1 receptor; TXA2: thromboxane A2; TxAS: thromboxane A synthase; UDP: uridine diphosphate; UDPGA: uridine-5′-diphospho-glucuronic acid; UGT: uridine 5′-diphospho-glucuronosyltransferase; VDR: vitamin D receptor

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