Multitarget PPARγ agonists as innovative modulators of the metabolic syndrome

European Journal of Medicinal Chemistry 173 (2019) 261e273

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European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech

Mini-review

Multitarget PPARg agonists as innovative modulators of the metabolic syndrome Alessandra Ammazzalorso, Cristina Maccallini*, Pasquale Amoia, Rosa Amoroso Department of Pharmacy, University of Chieti “G. d.Annunzio”, Via Dei Vestini, 31, 66100, Chieti, Italy

a r t i c l e i n f o

a b s t r a c t

Article history: Received 14 March 2019 Received in revised form 11 April 2019 Accepted 12 April 2019 Available online 13 April 2019

A multitarget pharmacologic approach could be advantageous for the therapy of metabolic multiple diseases, such as the metabolic syndrome, which is characterized by metabolic abnormalities associated with diabetes, obesity, hypertension, and increased cardiovascular risk. PPAR receptors play a critical role in metabolic disorders, affecting glucose and lipid metabolism. Drugs simultaneously targeting PPAR and other validated metabolic targets, represent a promising multitarget approach to combine antihyperglycemic, antihyperlipidemic, and antihypertensive effects. This review offers a survey of recently developed multitarget PPARg agonists as antidiabetic and antihypertensive drugs. © 2019 Elsevier Masson SAS. All rights reserved.

Keywords: Multitarget drugs Metabolic syndrome PPAR SUR FFAR1 GK PTP1B AT1 receptor sEH

1. Introduction Metabolic syndrome (MS) is a clinical multifactorial disorder, commonly found in obesity, characterized by interrelated abnormalities, such as hyperglycemia, hypertension, and dyslipidemia [1]. It represents an important risk factor for the development of type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD) [2]. The MS is often associated with incorrect lifestyle, poor physical exercise, inappropriate diet, stress, and excessive alcohol consumption. In particular, there is a strong association between the risk of developing MS and obesity. Besides the environmental influences and lifestyle, a role in the development of MS can also be attributed to genetic determinants, though their role has not been fully elucidated so far [3]. Although there are divergences in the medical field as for terminology, definition, and diagnosis for identification of MS, in 2009 a harmonized definition was established, with at least 3 or more criteria required for diagnosis: abdominal obesity, elevated triglycerides, reduced high density lipoprotein cholesterol (HDL-C), elevated blood pressure, and

* Corresponding author. E-mail address: [email protected] (C. Maccallini). https://doi.org/10.1016/j.ejmech.2019.04.030 0223-5234/© 2019 Elsevier Masson SAS. All rights reserved.

impaired fasting glucose (Fig. 1) [4]. MS is a multifaceted health problem and the approaches to treat this condition are both non-pharmacological and pharmacological. Non-pharmacological therapy includes lifestyle modifications, with weight loss and increased physical exercise, supported by psychological interventions, if necessary [5]. However, pharmacological treatments are often needed in people with MS, due to great difficulty in most patients to maintain substantial weight loss or a regular exercise program. In general, a multifactorial pharmacologic approach is aimed to modify the metabolic abnormalities associated with diabetes and reduce cardiovascular risk [6]. The most commonly prescribed drugs are anti-obesity drugs, thiazolidinediones (TZDs), metformin, statins, fibrates, angiotensin-converting-enzyme (ACE) inhibitors or angiotensin receptor 1 (AT1 receptor) antagonists, glucagon like peptide-1 (GLP-1) agonists, sodium glucose transporter-2 inhibitors, and some antiplatelet agents. Moreover, there are also emerging drug targets that may prompt novel therapeutic approaches, such as aquaporins, involved in adipose tissue homeostasis [7], protein tyrosine phosphatase, which reduces endothelial dysfunction in different cardiovascular diseases related to metabolic disorder [8], and inducible Nitric Oxide Synthase (NOS), implicated in hypertension and CVD [9e11].

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Abbreviations MS Metabolic syndrome T2DM type 2 diabetes mellitus CVD cardiovascular disease HDL-C high density lipoprotein cholesterol TZDs thiazolidinediones ACE angiotensin-converting-enzyme AT1 receptor angiotensin receptor 1 GLP-1 glucagon like peptide-1 NOS nitric oxide synthase PPARs peroxisome proliferator-activated receptors

Fig. 1. Harmonized definition of the MS. Adapted from ref. 4.

Within the multifactorial imbalance related to the MS, the peroxisome proliferator-activated receptors (PPARs), involved in the regulation of metabolic homeostasis, are validated therapeutic targets; in fact, PPARs are also called “lipid and insulin sensors”. PPARs are transcription factors activated by dietary fatty acids and endogenous lipid metabolites that regulate lipid and glucose utilization or storage in mammals [12]. Moreover, in recent years, several studies have demonstrated their key role in the regulation of vascular endothelium functions, mainly through the reduction of endothelial oxidative stress and the consequent increase of nitric oxide bioavailability [13]. The three characterized PPAR isoforms (PPARa, PPARg, and PPARb/d) share significant sequence homologies, but exhibit diverse functions and different tissue distributions. PPARa activation stimulates fatty acid transport and mitochondrial b-oxidation in liver, heart and skeletal muscle, PPARg regulates adipogenesis as well as glucose uptake and lipid biosynthesis in white adipose tissue, and PPARb/d has emerged as regulator of lipid metabolism and energy balance in adipose tissue, skeletal muscle, and the heart [14].

LBD SUR DPP-4 FFAR1 GPR-40 GK PTP1B SHR NEFA EETs sEH DHETs

ligand binding domain sulfonylurea receptor dipeptidyl peptidase-4 free fatty acid receptor 1 G-protein-coupled receptor 40 glucokinase protein tyrosine phosphatase 1B spontaneous hypertensive rats non-esterified fatty acids epoxyeicosatrienoic acids soluble epoxide hydrolase dihydroxyeicosatrienoic acids

Due to their role in human metabolic diseases, a number of selective PPAR synthetic agonists have been developed and displayed clinical effectiveness in treating T2DM and lipid disorders. PPARa agonists such as fenofibrate, ciprofibrate, bezafibrate, and gemfibrozil, are used in clinical therapy to treat dyslipidemia [15,16], while PPARg is the target of TZDs [17], such as rosiglitazone and pioglitazone, with potent therapeutic benefit for the T2DM. In addition to the commercially available compounds, numerous compounds targeting PPARs have been developed in the last years. Efforts to improve the clinical profile of fibrates or TZDs led to the synthesis of more selective PPARa agonists [18e20], and dual PPARa/g agonists [21e23], respectively. Other compounds developed in recent years include the pan-PPAR agonists [24e26] and selective antagonists [27e29], that exhibited different pharmacological activities. Furthermore, in silico docking studies revealed the binding modes in the ligand binding domain (LBD) of PPARs for many compounds, contributing to the important objective to discover new promising therapeutic compounds for MS (Fig. 2) [30,31]. Some PPAR agonists are currently under evaluation in clinical trials [32,33]. Recently, the complexity of pathological states has led to consider the pharmacological modulation of multiple biological targets, opening the way to the rational design of drugs with a superior therapeutic effect, but less toxic [34]. Multitarget drugs combine in their structures two or more drugs capable to interact with different mechanisms of action on different biological targets. Drugs of this kind can be “conjugated”, when two chemical entities are directly connected or separated by a linker, or “merged”, when two frameworks are integrated into a single molecular scaffold [35]. The polypharmacology approach to the discovery of new multitarget drugs is closely linked to a rational design supported by knowledge in different disciplinary fields, as computational modeling, synthetic chemistry, pharmacology, biology, and clinical studies [36]. This polypharmacology concept may be an attractive option for the therapeutic treatment of MS; in fact, designing drugs with a specific multitarget profile could improve the glycolipid metabolism and prevent the cardiovascular complications linked to hyperglycemic and hyperlipidemic conditions. In this context, the PPAR dual agonists or the pan-agonists (acting on different isoforms of the same receptor) can be considered multitarget compounds, even if this designation can be extended to molecules active on PPAR and other targets [37,38]. In this review, we will discuss the crosstalk of PPARg and other metabolic targets in the MS. In particular, we will illustrate compounds obtained by incorporating various pharmacophores or replacing the groups into known PPARg ligands, with the aim to modulate simultaneously multiple targets, with a synergistic effect on T2DM and hypertension. Fig. 3 offers a general overview of the structural modifications

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Fig. 2. PPAR ligands in therapy and under research.

Fig. 3. Structural modifications exploited on PPARg pharmacophore for designing dual targeting PPARg agonists.

exploited on PPARg pharmacophore to obtain multitarget PPARg agonists. 2. Multitarget PPARg agonists as antidiabetic drugs Major therapeutic options for the treatment of T2DM include drugs able to increase insulin secretion (secretagogues) or ameliorate insulin sensitivity (insulin sensitizers) [39]. Sulfonylureas and meglitinides are examples of secretagogues, while TZDs and metformin enhance insulin utilization in tissues. Since the late 1990s, TZDs represent a major therapeutic option for the management of T2DM, thanks to anti-hyperglicemic effects mediated by PPARg, affecting key genes involved in glucose and lipid metabolism [40]. Secretagogues and insulin sensitizers have been currently used for the management of diabetes, being able to

induce anti-hyperglycemic effects; moreover, they show a number of side effects, sometimes compromising the patient's life quality. Major undesired effects of traditional antidiabetic drugs include gastrointestinal problems, hypoglycemia, weight gain, edema, cardiovascular failure, increased risk of bone fractures. In the last years, the emerging knowledge about molecular mechanisms driving the complex pathology of T2DM led to the discovery of novel and interesting targets, as sulfonylurea receptor (SUR), dipeptidyl peptidase-4 (DPP-4) [41], GLP-1 receptor, free fatty acid receptor 1 (FFAR1, also known as GPR-40, G-proteincoupled receptor 40) [42e44], glucokinase (GK) [45] and protein tyrosine phosphatase 1B (PTP1B) [46]. Moreover, given the complexity and the multifactorial aspects involved in T2DM, a multitarget approach has been also pursued by many researchers, in the attempt to obtain multiple effects.

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In next paragraphs, the development of dual PPARg/SUR, PPARg/ FFAR1, PPARg/GK agonists and PPARg agonists/PTP1B inhibitors will be discussed.

located in pancreatic b cells, it promotes the closure of ATPsensitive potassium channels, stimulating the insulin secretion [48]. Interestingly, some second and third generation SUR agonists, as glipizide and glimepiride, showed the ability to activate also PPARg [49,50]. This is not completely surprising, considering that both PPARg and SUR agonists show similar structural motifs. Pharmacophoric models developed for PPAR and SUR agonists show a great similarity: the basic structural features of SUR agonists are three lipophilic centers connected by an amidic and an anionic linker, whereas the pharmacophoric model for PPARg agonists is formed by an acidic head, an aromatic portion and a lipophilic tail, connected by linkers (Fig. 4) [51]. This structural similarity led researchers to develop novel molecules able to simultaneously activate both receptors, inducing a potent anti-hyperglycemic action. Sulfonylureas containing a quinoxaline (1) or quinazoline nucleus (2,3) were synthesized as dual PPARg/SUR agonists (Fig. 5). The in vitro evaluation of these compounds showed good binding properties for both receptors; the in vivo experiments, in streptozotocin-induced hyperglycemic rats, produced a significant anti-hyperglycemic activity for many of compounds synthesized [51,52].

2.1. Dual PPARg/SUR agonists

2.2. Dual PPARg/FFAR1 agonists

Fig. 4. Pharmacophoric models developed for PPARg and SUR agonists. Adapted from ref. 44.

SUR is the molecular target of antidiabetic sulfonylureas [47];

FFAR1, also known as GPR40, a member of the G-protein-

Fig. 5. Quinoxaline (1) and quinazoline-based (2, 3) sulfonylureas as dual PPARg/SUR agonists. Activity data are reported as IC50 for PPARg and EC50 for insulin secreting activity.

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coupled receptor family, has been identified in the last years as a novel therapeutic target for diabetes [53]. It is mainly expressed in pancreatic b cells, and its stimulation by endogenous or synthetic ligands enhances the glucose-dependent insulin secretion [54]. FFAR1 is also expressed by endocrine cells in gastrointestinal tract, where it promotes the secretion of incretins, such as GLP-1. This double mechanism to control glucose homeostasis makes FFAR1 a target extremely interesting to develop innovative drugs for diabetes. Given that the action controlled by FFAR1 is dependent by glucose levels, FFAR1 ligands might not increase the risk of hypoglycemia induced by standard drugs promoting insulin secretion. The co-administration of an insulin sensitizer and an insulin secretagogue has been proposed as an efficient way to control hyperglycemia in diabetic patients: the associations glimepiride/ metformin (Amaryl M™) and glibenclamide/metformin (Glucovance™) are currently used in antidiabetic therapy. In line with these observations, researchers have been studying the possibility to obtain novel antidiabetic drugs acting on two different mechanisms of action, targeting both insulin secretion and sensitivity. From these studies emerged the PPARg/FFAR1 dual agonists as novel promising drugs. As observed for PPARg/SUR agonists, also in this case the structural requirements needed to activate PPARg and FFAR1 are very similar. In fact, a typical FFAR1 agonist consists of an acidic head, linked to an aromatic center, a heteroaryl linker, and a hydrophobic tail. Generally, FFAR1 agonists have a carboxylic moiety as acidic head; indeed, studies demonstrated the capability of TZDs to

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activate this receptor [55]. Recently, an Egyptian research group proposed novel TZDs as PPARg/FFAR1 dual agonists; in these molecules, the benzyl thiazolidindione was retained, connected by an alkylic spacer to hydrophobic tails. This screening campaign led to the discovery of benzhydrol (4) and indole-based (5) PPARg/ FFAR1 dual agonists, with most promising compounds illustrated in Fig. 6. They showed a balanced binding affinity on both targets at micromolar concentrations, and a significant anti-hyperglycemic and anti-hyperlipidemic action in vivo with respect to rosiglitazone [56]. A series of benzimidazole-based carboxylic acids were developed as dual PPARg/GPR40 agonists; compound 6a (Fig. 6) showed a balanced activity on both targets by mRNA expression analysis [57]. Its ester prodrug 6b showed a good anti-hyperglycemic effect in a diabetic mice model, making this novel compound a promising antidiabetic molecule. Recently, some authors reported the discovery of novel pan agonists active on PPARg, PPARd and FFAR1 [58]. Combining the structure of a PPARd agonist (7) and the FFAR1 agonist TAK-875 (8), a series of hybrids was obtained, resulting in the discovery of the lead compound 9 (Fig. 7). It showed a balanced activity on three targets and a significant hypoglycemic effect in normal and ob/ob mice, administered at 100 mg/kg. A similar strategy of combination led to the discovery of first-inclass PPARd/FFAR1 agonists, showing a promising antidiabetic activity in ob/ob mice and a favorable pharmacokinetic profile [59].

Fig. 6. Benzhydrol-based (4), indole-based (5) thiazolidinediones, and benzimidazole-based carboxylic compounds (6) as dual PPARg/FFAR1 agonists. Activity data are reported as fold activation (FA) or EC50 for human PPARg and EC50 for FFAR1.

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Fig. 7. Development of pan agonist PPARg/PPARd/FFAR1 (9). Activity data are reported as EC50 for human PPARg, PPARd and FFAR1.

2.3. Dual PPARg/glucokinase agonists GK, mainly expressed in liver and pancreatic b cells, plays a critical role in glucose metabolism and insulin secretion. This enzyme, in fact, catalyzes the glucose phosphorylation, the first step in the glycolytic process; in addition, its activity in pancreatic b cells is responsible for the glucose-stimulated insulin secretion. Through its mechanism of action, GK contributes to the glucose homeostasis acting as a “glucose sensor”, and interfering with insulin secretion and hepatic glucose metabolism. For these reasons, in recent years GK emerged as a promising target for monotherapy or combination therapy in T2DM [45,60]. In the attempt to identify novel multitarget antidiabetic drugs, researchers fused structural features of GK activators and PPARg agonists to obtain a combined action on both targets, expecting as a result an enhanced insulin secretion, a controlled glucose metabolism, and an improved insulin sensitivity. A series of dual GK/ PPARg agonists has been described, obtained by the combination of the benzamide GK activator by Merck-Banyu (10) and the PPARg agonist MK-767 (11) (Fig. 8). The designed dual target ligands (12) show the classical thiazolidinedione moiety, an aromatic center, an amide linker, and a 2amino nitrogen heteroaromatic system. From a large library of synthesized compounds, derivatives 12a-c emerged, showing high

potency for GK activation and moderate PPARg agonism [61]. A series of urea derivatives has been designed and tested as dual GK/PPARg agonists. Compounds were designed starting from classical structure of ureidofibrates, with benzothiazole (13, 14) or thiazole (15) as urea substituents (Fig. 9). Best compounds showed a good activation profile on both targets, and a moderate ability to decrease blood glucose in in vivo models [62]. Same authors reported on an interesting study on the antidiabetic activity of SHP289-03 (16), a dual GK/PPARg activator derived from nicotinic acid (Fig. 10) [63]. In vivo studies were carried out using the T2DM murine model KKAy: compound 16 decreased blood glucose levels, improved glucose tolerance and reduced blood lipid levels. The combined action on glucose metabolism, insulin sensitivity and lipid blood levels makes this compound a promising therapeutic option for T2DM treatment. 2.4. Dual PPARg agonists/PTP1B inhibitors The protein tyrosine phosphatase PTP1B has emerged as an attractive target for the treatment of T2DM and associated metabolic diseases, given its established role as negative regulator of insulin and leptin signaling [64]. A number of promising PTP1B inhibitors were developed in last years, with some of them progressed to clinical evaluation. Some TZD derivatives were reported

Fig. 8. Dual GK/PPARg activators (12) as novel antidiabetic drugs. In red is reported the essential pharmacophoric element responsible for PPARg activation, and in blue the one responsible for GK activation. Activity data are reported as efficacy % for PPARg (with respect to rosiglitazone) and fold activation (FA) for GK. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

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Fig. 9. Benzothiazole (13, 14) and thiazole (15) ureidofibrates as GK/PPARg dual activators. In red is reported the essential pharmacophoric element responsible for PPARg activation, and in blue the one responsible for GK activation. Activity data are reported as efficacy % for PPARg (with respect to rosiglitazone) and fold activation (FA) for GK. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 10. Chemical structure of the dual GK/PPARg agonist SHP289-03 (16). Activity data are reported as efficacy % for PPARg (with respect to rosiglitazone) and fold activation (FA) for GK.

as PTP1B inhibitors, able to induce antihyperglycemic and antiobesity effects [65]. Derivatives 17 and 18 (Fig. 11) represent the most promising compounds, obtained by an extended SAR study on benzylidene-2,4-thiazolidinediones [66]. They showed a PPARg activity comparable to rosiglitazone and a micromolar inhibitory potency on PTP1B; the in vitro evaluation of 18 in high fat dietinduced diabetic mice significantly suppressed weight gain and improved lipid parameters in serum. 3. Multitarget PPARg agonists as antihypertensive drugs Hypertension and insulin resistance are intimately linked, and constitute two components of the MS [67]. Currently, the therapy of

Fig. 11. Chemical structure of the dual PPARg agonists/PTP1B inhibitors 17e18. Activity data are reported as EC50 for PPARg and IC50 for PTP1B.

these two comorbidities is based on the combination of pharmaceutical agents targeting them separately, such as biguanides, solfonylureas, and TZDs to control diabetes, and diuretics, beta blockers, ACE inhibitors and AT1 antagonists to treat hypertension. Nevertheless, the prescription of different therapeutics often leads to issues with medical compliance and unforeseen drug-drug interactions, with an unfavorable pharmacokinetic and pharmacologic complexity. Therefore, to overcome the polypharmacy problems, dual agents able to normalize blood pressure and glucose and lipid metabolism simultaneously are highly desirable.

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3.1. PPARg agonists/AT1 antagonists as dual agents targeting angiotensin II Telmisartan (19, Fig. 12) is a benzimidazole derivative that reflects the general AT1 ligand structural features; in particular, the nitrogen at position 3 of the central benzimidazole seems to be essential for AT1 antagonism, acting as an H-bond acceptor [68]. Differently from other AT1 blockers, i.e. losartan and valsartan, telmisartan improves glycemic parameters of MS patients, and this was reasonably attributed to its weak activity at PPARg [69]. So, the identification of telmisartan as an AT1 antagonist with selective PPARg modulating activity has opened the way to the research of new pharmaceutical agents with such therapeutic characteristics. The alkyl side chain at position 2 of the central benzimidazole ring and the lipophilic moiety at position 6 have been identified as structural requirements for PPARg receptor activation and cofactor recruitment [70]. In 2009, Chittiboyina et al. reported the synthesis of novel hybrids telmisartan-rosiglitazone as dual PPARg agonist/AT1 antagonists, but almost all the synthesized molecules showed moderate PPARg activation and were inactive as AT1 antagonists [71]. The best compound of this series was molecule 20, which gave moderate dual activation of PPARa/g and antagonism against the AT1 receptor (Fig. 12). Later, by means of a cross screening strategy of known PPARg agonists as AT1 blockers, and known angiotensin receptor antagonists as PPARg agonists, Pfizer disclosed an indanyl-based scaffold characterized by robust AT1 activity and partial activation of PPARg

(Fig. 13) [72]. It was demonstrated that the conformational restriction derived from the indane ring is required for PPARg activity, and that the R1 group is important to modulate activity against AT1 receptor. Moreover, S configuration at the indane asymmetric center is required. In particular, molecule S-21 emerged as the most promising compound (hPPARg EC50 212 nM and AT1 IC50 1.6 nM), demonstrating oral bioavailability and efficacy in animal models of hypertension and insulin sensitization. As development of the indanyl-based scaffold, a series of imidazo[4,5-c]pyridin-4-ones was also synthetized, but with a limited improvement in potency and SAR with respect to the indanyl scaffold. However, the introduction of a nitrile group (compound S22) improved not only the biological profile toward PPARg and AT1 receptor, but also the physicochemical and in vitro ADME properties (Fig. 13) [73]. Indeed, compound S-22 showed moderate in vitro human liver microsomes intrinsic clearance, high permeability, moderate kinetic solubility, and low potential for drug-drug interactions for cytochrome P450 isoforms. In the past years, GlaxoSmithKline demonstrated that the replacement of the telmisartan benzimidazole central core by an indole could give potent full PPARg agonists, but caused a drop in AT1 receptor affinity, as in compound 23 (hPPARg EC50 0.8 nM, and 31% of maximal activation with respect to rosiglitazone; AT1 IC50 > 10 mM) (Fig. 14) [74]. From the development of this latter structure, three series of compounds were synthesized: the reverse indole, the pyrazolopyridine and the indazole ones. From this latter, the butylbenzimidazole derivative 24 showed very interesting and selective agonism on hPPARg (EC50 0.25 mM) and potent AT1 receptor antagonism (IC50 6 nM). When in vivo administered, compound 24 was active at 10 mg/kg on blood pressure in the spontaneously hypertensive rats (SHR) model, and at a dose of 75 mg/kg it demonstrated similar effects on insulin, non-esterified fatty acids (NEFA) and triglycerides compared to the fully PPARg agonist GW1929 in Zucker fa/fa rats [75]. 3.2. PPARg agonists as dual agents targeting soluble epoxide hydrolase

Fig. 12. Structure of telmisartan and of the benzimidazole based compound 20. As for telmisartan, in red are reported structural moieties responsible for PPARg activation, while nitrogen in blue is an Hebond acceptor essential for AT1 antagonism. Activity data are reported as EC50 or FA for hPPARg, IC50 or Ki for AT1 receptor. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Epoxyeicosatrienoic acids (EETs) are produced in endothelial cells and play important roles, activating Ca2þ-activated Kþ channels on smooth muscle, and leading to hyperpolarization and vascular relaxation [76,77]. Soluble epoxide hydrolase (sEH) is an enzyme of the arachidonic acid cascade catalyzing the hydrolysis of bioactive EETs to the less active dihydroxyeicosatrienoic acids (DHETs). Different studies have demonstrated that the selective inhibition of sEH could increase the concentration of EETs, leading to positive effects on various disorders associated to the MS [77]. Indeed, it was observed that the inhibition of sEH augments the islet glucose-stimulated insulin secretion in diabetic mice [78], and positively influences water and electrolyte homeostasis. The latter effect could balance the main side effects of TZDs, i.e. weight gain and edema due to water retention. Almost all reported sEH inhibitors are epoxide mimetics, containing an urea or an amide structure as pharmacophore. In Fig. 15 are depicted the reported sEH inhibitors AUDA (25), tAUCB (26), and GSK2188931B (27). Recent studies indicated that EET biological effects could be mediated by PPARg, which subsequently promotes the expression of sEH [79,80]. Thus, considering the significant degree of crosstalk between PPARg and sEH, the combination of PPARg agonism and sEH inhibition in one compound might be beneficial for the treatment of MS. In fact, a combination of the sEH inhibitor 26 and rosiglitazone efficiently restored insulin sensitivity, lowered blood pressure, and protected rats from nephropathy [81]. In a first effort to obtain dual modulators of hEH and PPARg, E. Proschak's research group synthesized a series of cyclohexyl-,

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Fig. 13. General structure of the indanyl-based dual agents disclosed by Pfizer and chemical structure of the most interesting compounds S-21 and S-22. In red is reported the essential pharmacophoric element responsible for PPARg activation, and in blue the one responsible for AT1 antagonism. Activity data are reported as EC50 for human PPARg, and IC50 for AT1 receptor. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

adamantyl or p-trifluoromethoxy-phenyl ureas, linked through an aromatic spacer to a carboxylic acid headgroup (Fig. 16) [82]. This latter is an important requirement to achieve PPAR agonism, while the hydrophobic urea group was introduced as an epoxide mimetic. The most interesting compounds were the adamantyl derivatives, as they selectively activated PPARg, and compound 28 gave the best results (PPARg EC50 6 mM, and sEH IC50 0.178 mM). Probably, the adamantly group fits the PPARg larger left distal ligand binding pocket, compared to the other receptor subtypes. Later, the same research group synthesized a series of benzylamide derivatives as dual sEH/PPARg ligands (Fig. 17), starting from the observation that the benzylamide group of the PPARg agonist GSK1997132B (29, Fig. 17) is able to replace the pharmacophoric acidic headgroup of typical PPARs ligands, and that this moiety can also be found in sEH inhibitors, such as in GSK2188931B (Fig. 14) [83]. From the activity evaluation of these new compounds, emerged interesting SAR: 1) small substituents in R1 increase sEH activity. The phenoxy group increases activity toward PPARg, but it is not tolerated by sEH; 2) the presence of o-trifluoromethyl- or o-trifluorometoxy group is essential for sEH activity; 3) para or meta substitution of the benzylamide improves sEH inhibition, while the p-substitution is preferred by PPARg; 4) there is little influence on sEH and PPARg potency if R3 is larger than the methyl group; 5) it is

possible to increase sEH inhibition introducing a-b-unsaturation with respect to the carboxylic acid; 6) the carboxylic acid improves potency on PPARg and pharmacokinetics. From this SAR study, compound RB394 (30, Fig. 17) emerged as the most interesting compound, as it was a potent, water soluble, dual sEH/PPARg modulator endowed with favorable ADME profile. It was able to in vivo upregulate PPARa and PPARg, as well the PPARg target genes. Very recently, it was reported that RB394 prevents the development of metabolic abnormalities and kidney injury in a model of MS, ameliorates T2DM, and reduces multiple diabetic complications [84]. 4. Conclusion Being inherently multifactorial, the MS might benefit from a multitarget approach, characterized by the ability of a molecule to interact with multiple targets simultaneously, providing a wider pharmacological spectrum. The present review shows examples of dual-acting PPARg agonists, obtained by incorporating various pharmacophores or replacing the groups into known PPAR ligands. It is divided into two sections: in the first part, useful compounds were identified to modulate, in addition to PPARg, also the SUR and FFAR1 receptors, as well as GK and PTP1B, with the aim to induce a potent antidiabetic effect. In the second section, compounds acting

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Fig. 14. Dual agents developed at GlaxoSmithKline. Activity data are reported as EC50 and efficacy % with respect to Rosiglitazone for human PPARg, and IC50 for AT1 receptor.

Fig. 15. Chemical structure of soluble epoxide hydrolase inhibitors 25e27. In blue is reported the essential pharmacophoric element for sEH inhibition. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

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 E. et al. and of the most interesting compound 28. In red is reported the pharmacophoric moiety responsible Fig. 16. Chemical structure of the ureidic scaffold reported by Buscato for PPARg activation, and in blue the one responsible for sEH inhibition. Activity data are reported as EC50 for PPARg, and IC50 for sEH. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 17. Chemical structure of the PPARg agonist GSK1997132B and of the developed benzylamide scaffold. In red is reported the pharmacophoric moiety responsible for PPARg activation, and in blue the one responsible for sEH inhibition. Among this series of dual sEH/PPARg ligands, compound 30 (RB394) emerged as the most interesting molecule. Activity data are reported as EC50 for PPARg, and IC50 for sEH. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

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