Urea Derivatives in Modern Drug Discovery and Medicinal ...

The urea functionality is inherent to numerous bioactive compounds, including a variety of clinically approved therapies. Urea containing compounds are increasingly used in medicinal chemistry and drug design in order to establish key drug-target interactions and fine-tune crucial drug-like properties. In this perspective, we highlight physicochemical and conformational properties of urea derivatives. We provide outlines of traditional reagents and chemical procedures for the preparation of ureas. Also, we discuss newly developed methodologies mainly aimed at overcoming safety issues associated with traditional synthesis. Finally, we provide a broad overview of urea-based medicinally relevant compounds, ranging from approved drugs to recent medicinal chemistry developments.

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In recent years, urea containing compounds have received much attention due to their growing application in drug design and medicinal chemistry. 25 , 26 In the present perspective, we plan to outline physicochemical properties of urea derivatives, highlighting the key role of the urea functionality in the drug-target interaction. We outline the chemical methodologies for the synthesis of urea derivatives. We cover the most recent methodologies that highlight the progress in terms of both process safety and efficiency. Finally, we provide a broad overview of the relevance of the urea functionality and urea derivatives in modern drug discovery and medicinal chemistry.

Beyond their presence in approved drugs, oligoureas play a pivotal role as starting motifs for the generation of artificial β-sheets 16 , 17 and peptidomimetics. 18 , 19 Urea derivatives are also widely employed as linkers for the development of antibody-drug conjugates as well as in combinatorial chemistry building blocks. 20 , 21 Due to the importance of urea derivatives in the syntheses of medicinal agents and other applications in material science and organocatalytic reactions, a variety of methods have been developed for their syntheses. 22 , 23 Traditional syntheses of urea-containing compounds involve the reaction of amines with phosgene, carbon monoxide, or isocyanates. However, these synthetic procedures have relevant safety and environmental issues due to the use of toxic agents. Alternative routes involving reactions of amines with less toxic agents such as ethylene carbonate or diethyl carbonate have been developed. Also, many other direct routes to urea derivatives from amines and CO 2 in the presence of numerous catalysts were investigated. A number of ionic liquids were also examined as suitable solvents for the syntheses of urea derivatives. 24

One of the early examples of urea derivatives as a medicinal agent is the development of compound 3 by Bayer&#;s laboratories in Germany. Urea derivative 3 is a colorless derivative of trypan red and has shown potent antitrypanosomal activity. Further optimization of urea compound 3 led to the discovery of suramin ( 4 ) with potent antitrypanosomal properties. Suramin is used as an effective therapy during the early stage of sleeping sickness in humans that is caused by the protozoan parasites T. Gambiense and T. Rhodesiense. 9 , 10 Urea-derived Glibenclamide ( 5 ), also known as glyburide, is a potent antidiabetic drug that prolongs the hypoglycemic effect. It was used to treat patients with type II diabetes. 11 Today, there are many urea containing compounds that are FDA approved drugs for a variety of human diseases. 12 &#; 15 We will outline these approved therapies in the next section.

The synthesis of urea by the German chemist Fredrich Wöhler in marked the beginning of organic chemistry. 1 , 2 Since then, rapid evolution of organic chemistry and further developments in synthesis enabled medicinal chemistry and drug discovery in the latter half of the 20th century. 3 , 4 Urea and its derivatives ( 1 and 2 , Figure 1 ) have a central role in drug development and medicinal chemistry due to the capability of the urea functionality to form multiple stable hydrogen bonds with protein and receptor targets. Such drug-target interactions are responsible for specific biological activity, drug actions, and drug properties. It is not surprising that a large number of urea derivatives are utilized in a broad range of medicinal applications. In particular, a urea functionality is incorporated to modulate drug potency and selectivity and improve drug properties in the development of anticancer, antibacterial, anticonvulsive, anti-HIV, antidiabetic agents, and other medicinal compounds. 5 , 6 With the advances of protein structures and identification of new disease targets, there is a growing interest in urea-based derivatives for drug design and development. 7 , 8

Oligomeric aromatic ureas characterized by N,N&#;-dimethylated urea moieties display a multilayered structure due to the (cis,cis)-urea arrangement. Such derivatives, containing a chiral center on the R2 group, display a dynamic helical architecture (all-S or all-R axis configuration) in solution when the phenyl moieties are connected through urea linkages at the meta positions. These dual dynamic helical and aromatic multilayered properties can be exploited to construct aromatic functional molecules with unique physicochemical properties. 39 , 40

Employing N,N&#;-diaryl ureas to relay stereochemical information over long distances, thus achieving stereochemical control over conformation, is another important feature of this functional group. As shown in Figure 6 , reduction of N,N&#;-diaryl urea 11 containing a chiral sulfinyl group proceeded with excellent diastereoselectivity, providing alcohol 13 as the major diastereomer (dr 95:5), even though the chiral sulfinyl group is localized many bond lengths away. Presumably, the observed remote diastereoselectivity is due to the defined conformation of the chiral N,N&#;-diaryl urea 12 which resulted in the preferential nucleophilic attack from the Re-face of the carbonyl center affording alcohol 13 . 38

More recent studies on the conformational preferences of urea derivatives employing a combination of IR, NMR, and computational studies (DFT-D, M06&#;2X, quantum calculations, molecular dynamics) highlighted a more dynamic behavior of the N,N&#;-aryl ureas and N,N&#;-diaryl-N,N&#;-dialkyl ureas, although still in favor of the predominant isomer from the solid state studies. 33 , 34 In studies with synthetic retinoids and cytokinins, the stereochemical alteration following N-methylation of aromatic amides was utilized in modulating the biological activity. 35 Similarly, stereochemical switching through N-methylation of ureas from a transoid structure to the preferred bis-cis-N,N&#;-dimethyl-N,N&#;-diphenylureas has been exploited. This strategy is particularly attractive in molecular design due to ease of introduction of the N-methylurea substructure in organic molecules. As shown in Figure 5 , the N,N&#;-dimethyl-N,N&#;-dinaphthylurea ( 9 ) and N-methyl derivative of poly-(phenyleneureido)benzene ( 10 ) formed nice π-stacked aromatic arrays as observed based upon NMR and X-ray crystallographic studies. 36 This concept has been successfully applied to the construction of conformationally defined oligomers (foldamers) and dynamic helical structures as biomimetics. 37

Theoretical studies suggest that the conformation showing the two aromatic rings with a face to face disposition in a mirror image relationship is disfavored as shown in Figure 4 . The X-ray structural studies revealed a staggered relationship where the overlap of the HOMO of one ring with the LUMO of the other is enhanced ( Figure 4 ). 31

Extensive NMR studies and ultraviolet spectra analysis in solution on several substituted diphenylureas were performed to obtain insight into the stacking of the aromatic rings. Interestingly, the conformation from the X-ray crystallographic data and the conformations adopted in solution are in good agreement. These studies supported similar hybridization of the nitrogens and relative positions of the aromatic rings. 31 , 32

Substitution on the nitrogen atoms of the urea moiety plays a key role on the conformational preferences of urea derivatives. 28 As shown in Figure 3 , three conformations ( 6a - c ) are possible for N,N&#;-diphenylureas. In solution and in solid state, they are generally characterized by a trans,trans conformation. 29 , 30 Interestingly, sequential introduction of N-methyl group(s) to the free NHs of N,N&#;-diphenylurea prompted the shift from trans,trans ( 7 ) to cis,cis ( 8a ) conformation. Thus, N,N&#;-diaryl-N,N&#;-dimethylurea exhibits intrinsic preference for a cis,cis conformation ( 8a ) over trans,cis conformation ( 8b ), characterized by the two aromatic portions located in a face-to-face arrangement, thus allowing π-π stacking interactions. 28

The urea functionality shows a certain degree of conformational restriction due to the presence and delocalization of nonbonded electrons on nitrogens into the adjacent carbonyl group. Accordingly, three resonance structures can be drawn for ureas (namely A, B, and C; Figure 2 ). 27 Data on the X-ray structure of N,N&#;-diphenyl-N,N&#;-diethylurea revealed that the two urea nitrogens adopt a geometry between trigonal and tetrahedral. The amide groups displayed a nonplanar distortion of approximately 30° with amide C-N bond lengths of 1.37 Å. 27

Urea-assisted RNA unfolding is another phenomenon which can be explained by the engagement of an extrahelical state via favorable π-π, NH-π, and hydrogen bonding interactions with the urea moiety. Both urea and water can establish NH-π and hydrogen bonding interactions with nucleic acid structures. However, stacking interactions are only possible with urea, and this explains its strong denaturing actions. These effects also rely upon the base composition and nature of nucleic acids. 64 , 65

(A) Representation of the stacking interaction between Trp6 and urea; (B) NH-π interaction between the tryptophan 6 side-chain and urea. Part of the Trp-cage miniprotein is shown in magenta; carbon atoms, nitrogen, and hydrogen atoms are shown in green, blue, and yellow, respectively. The figure is modified based upon published structures. 61

The aromatic ring stacking interactions play an important role in urea-assisted protein denaturation. Using Trp-cage mini-protein, Priyakumar and co-workers 61 investigated distortion of the protein hydrophobic core in the presence of urea and showed that aqueous urea optimally solvates aromatic groups in the protein. Furthermore, studies suggested the presence of stacking and NH-π interactions involving aromatic groups and urea. In particular, three kinds of interactions were shown between the Trp6 side-chain and urea: (i) stacking, where the urea moiety and indole ring were parallel to each other, (ii) NH-π interaction, where one of the NH bonds of the urea was perpendicular to the indole ring; (iii) typical hydrogen-bonding interaction between the urea oxygen atom and the nitrogen atom of the Trp side chain. Stacking and NH-π interactions with urea are responsible for stabilizing Trp6 in the unfolded state ( Figure 11 , PDB ID: 1L2Y). 61

Several protein structures in the Protein Data Bank contain urea and urea derivatives as ligands or cosolvents. Quite interestingly, 38% of the structures containing urea and 25% of those containing urea derivatives were found to fall within the geometric requirements for a stacking arrangement with aromatic rings (e.g., PDB ID: 3IPU and 4EV9). 59 , 60 The relevance of stacking interactions between urea and aromatic side chains in urea transporters (UTs) has been modeled by Priyakumar and co-workers. 61 UTs are trimeric transmembrane proteins with a parallel arrangement of aromatic rings in the pore which allows stacking of urea and urea homologues (e.g., formamide, acetamide, and dimethylurea). This results in lowering of the energy barrier for urea based solute to transport. 62 , 63

Although the hydrogen bonding ability of the urea moiety has been long known and studied, this functionality can also be involved in other types of important interactions, especially those involving urea functionality and aromatic side chains in proteins. 56 , 57 Several crystal structures of proteins bound to urea/urea derivatives have been identified to exhibit π-stacking-like favorable interactions. Moreover, perpendicular orientation of urea with respect to aromatic groups leads to NH-π type interactions. Such a complex hydrophilic/hydrophobic combination of interactions involving the urea moiety could likely be exploited in the future design of ligand molecules for drug discovery purposes. 58

Another strategy to disrupt planarity is represented by the insertion of substituents at the ortho position of the N-aryl group of arylureas. Thus, the presence of two halogen atoms at the ortho position of the urea functionality could promote the formation of intermolecular hydrogen bonds due to a better conformational preorganization of the monomer. FT-IR and ab initio calculations revealed that an intramolecular hydrogen bond is formed when phenylureas are functionalized with chlorine or bromine atoms at the ortho positions. This halogen effect is at least in part due to the significant influence of the substituents on the dihedral angle (φ) between the urea functionality and the aromatic groups. As shown in Figure 10 , in the absence of substituents in compound 19 , the most stable conformation for the compound is coplanar (φ = 0°), while in the presence of chlorine or bromine substituents (compounds 20 and 21 ), the energy surface is completely flat with φ values ranging from 60° to 120°. 55

In this approach, water solubility is enhanced by disrupting the molecular planarity of the solutes in order to reduce their crystal packing energy. 51 The strategy involves the breaking of the urea symmetry by introducing a substituent on one of the urea nitrogens which disrupts planarity. 52 &#; 54 A practical example is shown in Figure 9 . N-Methyl-N-1-naphthyl urea ( 18 ) acts as a disruptor of cytokine-mediated STAT1 signaling in β-cells. Incorporation of a methyl group on the urea nitrogen of 17 provided N-methyl-N-1-naphthyl urea ( 18 ). The presence of a methyl group disrupts the existence of planar conformations, due to steric clash between hydrogens at C-2 or C-8 positions of the quinoline ring and the appended N-methyl group. Compound 18 showed a 110-fold solubility increase over compound 17 . This data also well correlated with a decreased melting point for compound 18 compared to compound 17 (~145 °C vs ~171 °C, respectively). 53

This strategy can be exploited to increase permeability and solubility with the formation of a transient or pseudoring structure. This can be achieved by engagement of a urea functionality in a novel monocyclic template that mimics a bicyclic structure. 48 As shown in Figure 8 , based on the structure of a bicyclic kinase inhibitor ( 15 ), a series of pyrimidin-4-ylureas ( 16 ) were designed. This monocyclic structural template could function as suitable bioisostere due to its tendency to form resonance-assisted intramolecular hydrogen bonds. 49 The feasibility of this approach was demonstrated since this compound class exhibits multikinase inhibitory activity. A cocrystal structure revealed the hypothetical binding mode. Furthermore, NMR and theoretical studies substantiated the existence of an intramolecular hydrogen bond and its existence in water medium. 50

In order to modulate hydrogen bonding capability, electron donating and electron withdrawing functionalities have been introduced on the substituents on the urea nitrogen atoms. The nature of aliphatic moieties placed on the urea nitrogen has been shown to affect self-association properties thus controlling drug solubility in nonpolar solvents. 46 A representative example is the N,N&#;-di(2,6-diisopropylphenyl)urea (DIPPU, 14 ) which is the only diaryl urea that is soluble in carbon tetrachloride among eight other symmetrical diaryl ureas examined. DIPPU does not form a supramolecular polymer. When the branched alkyl moieties are not too large, the corresponding dialkylureas self-assemble to form supramolecular polymers in solution ( Figure 7A ). 47 However, DIPPU stabilizes the out-trans conformation due to large steric bulk of the alkyl chain on the aromatic rings. Therefore, the formation of dimers occurs through hydrogen bonding of the N-H groups in the out conformation as shown ( Figure 7B ).

Hydrotropic solubilization involves the addition of one solute to promote the solubility of another and is a strategy explored in pharmaceutical formulations. Hydrotropes are mostly aromatic or nonaromatic anions but can also be represented by neutral compounds, such as ureas. 45 Hydrotropic solubilization strategy was employed for the solubilization of nifedipine, a poorly soluble antihypertensive drug, by a series of urea analogues in an aqueous environment. The solubilizing effect ranking followed the trend butylurea > ethylurea > methylurea > urea. 46 Sometimes, urea containing drugs show poor pharmacokinetic properties due to solubility and permeability issues. Many strategies have been developed to circumvent these issues. They are shown below.

The presence of a urea functionality plays an important role in a drug&#;s aqueous solubility and permeability due to its dual nature as a hydrogen bond donor and acceptor. For a central nervous system (CNS) acting drug, a moderate level of lipophilicity would allow the drug to cross the blood-brain barrier (BBB) by a passive diffusion process. The hydrogen bonding capability 42 in addition to ionization, polar surface area, and flexibility also strongly affects drug transport across the BBB. 43 , 44

The oral bioavailability of a drug depends upon many factors including solubility, dissociation, permeability, first-pass metabolism, and efflux properties. Drug solubility in water is vitally important for drug absorption, bioavailability, and drug administration. The development of appropriate formulations for poorly soluble drugs is a major challenge in drug design and development. The structure of a drug molecule typically contains multiple functional groups which determine the overall hydrophobic or hydrophilic nature of the molecule. This hydrophobic/hydrophilic balance affects the capability of a given drug to cross biological membranes. 41

Compound 29 contains a benzylidenepiperidine pyridazine urea. The X-ray and kinetic studies demonstrated that these urea-containing derivatives are able to covalently and irreversibly inhibit FAAH through involvement of the Ser241-Ser217-Lys142 catalytic triad as shown in Figure 18 . The urea functionality interacts with the catalytic Ser241 nucleophile, thus generating a tetrahedral intermediate ( 30 ) and sub-sequently inducing carbamoylation (inactivation) of the FAAH enzyme through formation of carbamate 31 . 83 , 84 Recently, PF- has been shown to reduce cannabis withdrawal symptoms and cannabis use, in a phase IIa clinical trial. 85

PF- ( 29 ) is a highly potent inhibitor of fatty acid amide hydrolase (FAAH). 79 FAAH is a serine hydrolase responsible for the metabolism of signaling lipids, such as the endocannabinoid anandamide. 80 FAAH is considered a potential therapeutic target for the treatment of pain and nervous system disorders. Thus, small-molecule FAAH inhibitors would exert their beneficial effects without the potential drawbacks associated with direct stimulation of cannabinoid receptors. 81 , 82

Another example of the key role of urea functionality in drug-target interactions is shown in urea-derived soluble epoxide hydrolase (sEH) inhibitors. The sEH is involved in the metabolism of endogenous mediators (e.g., epoxides of linoleic acid, arachidonic acid, and other lipids). 71 The catalytic mechanism of sEH as shown in Figure 17A , involves a SN2-type reaction in which the epoxide is first activated by forming hydrogen bonds with Tyr381 and/or Tyr465 residues. Subsequent nucleophilic attack by Asp333 forms the acylenzyme intermediate which is attacked by a water molecule activated by His523. The resulting tetrahedral intermediate finally collapses to provide the diol product ( Figure 17A ). 1,3-Disubstituted ureas have become interesting structural templates for sEH inhibition. 72 &#; 75 The X-ray structural studies with the urea-derived inhibitor 4-(3-cyclohexylureido)-ethanoic acid ( 28 ) demonstrated that the urea moiety is able to mimic the transition state of the sEH-catalyzed epoxide ring opening, establishing strong hydrogen bonding interactions with Asp333 and Tyr381 residues ( Figure 17B ). 76 &#; 78

Urea derivative 27 is a potent Map kinase inhibitor that has undergone human clinical trials for the treatment of inflammatory diseases. Interestingly, the N-pyrazole-N-aryl urea occupies the binding domain on p38 that is exposed when the conserved binding loop containing Asp168, Phe169, and Gly170 adopts a DFG-out conformation ( Figure 16 ). The X-ray structural studies revealed that both urea NHs form strong hydrogen bonds with the Glu71 side chain carboxylic acid while the urea carbonyl forms a strong hydrogen bond with the Asp168 backbone amide NH. The naphthalene moiety binds in the kinase specificity pocket. The ethoxymorpholine chain adopts a Gauche conformation and orients the morpholine oxygen to form a strong hydrogen bond with the backbone NH of Met109 in the ATP binding region of p38. 6

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The urea moiety also plays a prominent role in molecular recognition of sorafenib ( 25 ) and lenvatinib ( 26 ) by the protein kinase active site ( Figures 14 and 15 ). The X-ray crystal structures of vascular endothelial growth factor receptor 2 (VEGFR2) in complex with either lenvatinib or sorafenib were determined. These protein-ligand complexes with lenvatinib and sorafenib highlighted the importance of the urea functionality. As shown, the urea functionality is involved in critical hydrogen bonding with main-chain atoms of Asp and the side-chain atoms of Glu885 ( Figures 14 and 15 ). 70 The quinoline moiety of lenvatinib and the pyridine core of sorafenib

HIV protease inhibitors featuring a cyclic urea substructure have also been designed and developed into a number of preclinical candidates. One of the specific design objectives was to replace the structural water molecule found in cocrystal structures of HIV protease and linear inhibitors using the urea functionality. The resulting inhibitors maximized interactions in the protease active site and maintained good activity against mutant proteases. 68 Compound 24 (DMP450) and a number of other urea-based inhibitors exhibited broad spectrum antiviral activity against multidrug-resistant HIV-1 variants. 69 The cocrystal structure (PDB id: 1DMP) of DMP450-bound HIV-1 protease revealed that the urea functionality nicely mimicked the flap ligand-bridging water molecule ( Figure 13 ). Also, the conformationally locked cyclic core allowed optimal interaction and accommodation of ligands within the S1, S1&#;, S2, and S2&#; subpockets of the HIV protease active site. 68

A series of potent HIV protease inhibitors have been developed featuring a urea substructure. In , Getman and co-workers reported a novel class of HIV-1 protease inhibitors incorporating the (hydroxyethyl)urea isostere. Compound 22 (SC-) exhibited good inhibitory activity on HIV-1 protease (IC 50 = 6.3 nM) and excellent selectivity over other aspartyl proteases, such as renin and cathepsin D. As shown in Figure 12 , X-ray structural studies of a related inhibitor 23 containing a n-butyl chain complexed with HIV-1 protease revealed that the inhibitor binds in an extended conformation with the (R)-hydroxyl group positioned symmetrically between the two catalytic aspartates of the enzyme. The urea carbonyl group appears to be involved in water-mediated hydrogen bonding with the Ile50 and Ile50&#; residues. The P2&#; n-butyl substituent of the urea derivative is occupying the S1&#;-binding site, and the P1&#; isobutyl group has occupied the S2&#; subsite. 67

The bioactivity of drugs is governed by molecular recognition through drug and target protein interactions. Among the multiple forces that are involved in protein-ligand interactions, hydrogen bonds play a key role due to their ability to stabilize the drug-receptor interaction. 44 , 66 The donor-acceptor hydrogen bonding capability of urea derivatives is one of the most important elements of their molecular recognition and bioactivity. A few examples describing key interactions involving urea functionality in biologically active compounds are presented here.

RG ( 40 , Figure 19 ) is a urea-containing small-molecule acting as an MDM2 antagonist. MDM2 downregulates the tumor suppressor p53. 116 RG underwent a phase I clinical trial in patients with hematologic malignancies. The main goal of the study was the estimation of the posology and safety profile. The secondary goals involved the assessment of pharmacokinetics, pharmacodynamics, and preliminary clinical efficacy. 117 RG is mainly metabolized by CYP3A4/5 and also behaves as a moderate inhibitor of CYP3A4/5 and P-glycoprotein (P-gp). 118

Lenvatinib ( 26 , Figure 19 ) is a multi-kinase urea-based inhibitor targeting VEGF receptors 1&#;3, fibroblast growth factor receptors 1&#;4, PDGFR α, and RET and KIT proto-oncogenes. 110 &#; 112 Lenvatinib is approved for treating radioiodine-refractory differentiated thyroid cancer, and combined with Everolimus, it is used to treat advanced renal cell carcinoma. 113 Moreover, lenvatinib is under study for the treatment of hepatocellular carcinoma. The main metabolic products isolated from human liver microsomes derive from demethylation, decyclopropylation, O-dearylation, and N-oxidation. 114 CYP-related metabolism was reported in human, monkeys, dogs, and rats, while non-CYP-mediated metabolism, mainly ascribable to the action of aldehyde oxidase, has been found in monkeys and humans. 115

Carmofur ( 39 , HCFU, 1-hexylcarbamoyl-5-fluorouracil, Figure 19 ) is a pyrimidine analogue used as an antineoplastic agent, and it is an orally available lipophilic-masked derivative of 5-fluorouracil. Its carbamoyl moiety is cleaved in vivo to release 5-FU. Carmofur has been employed for the therapy of colorectal cancer, 107 although causing delayed leukoencephalopathy. 108 Significant side effects and no survival advantage in patients with stage II hepatocellular carcinoma led to clinical trial discontinuation. 109

Celiprolol ( 38 , brand names Cardem, Selectol, Celipres, Celipro, Celol, Cordiax, Dilanorm, Acer Therapeutics, Figure 19 ) is a β-blocker characterized by a unique pharmacologic profile: it behaves as a β1-andrenoceptor antagonist with partial β2 agonist activity. Based on these properties, it can be defined as a selective adrenoreceptor modulator with antihypertensive and antianginal properties. 104 Recently, the unique properties of celiprolol prompted investigation into its use for the treatment of a rare connective tissue disorder, namely Ehlers-Danlos syndrome. 105 Celiprolol is minimally metabolized, with only a very low percentage of a dose being excreted. 106

Zileuton ( 37 , Zyflo, Cornerstone Therapeutics Inc., Figure 19 ) is a benzothiophene N-hydroxyurea. It is an inhibitor of 5-lipoxygenase (5-LOX), and it alleviates allergic and inflammatory states by suppressing leukotriene biosyn-thesis. 101 , 102 Zileuton inhibits 5-LOX by coordinating the iron ion in the active site, and it also displays weak reducing properties. Zileuton and its N-dehydroxylated metabolite are oxidatively metabolized by CYP450 isoenzymes 1A2, 2C9, and 3A4. Interactions of zileuton with other drugs are related to inhibition of CYP1A2. 103

Telcagepant ( 36 , code name MK-, Figure 19 ) was a urea containing oral calcitonin gene-related peptide (CGRP) receptor antagonist launched by Merck as an investigational drug for the treatment and prevention of migraine; it was the first orally available drug in this class. 98 A Phase IIa clinical trial evaluating telcagepant for the prophylaxis of episodic migraine was halted on March 26, after the observation of a significant increase of serum transaminase levels upon treatment. 99 MK- undergoes significant oxidative metabolism (CYP3A) in monkey intestinal microsomes. The drug is mainly metabolized as pyridine N-oxide, and its metabolism is slower in rat than in monkey intestinal microsomes. 100

Cariprazine ( 35 , Vraylar in the United States and Reagila in Europe, Gedeon Richter and Actavis, Figure 19 ) is a urea-containing dopamine D3/D2 receptor partial agonist, acting as atypical antipsychotic for treating schizophrenia and bipolar disorders. 94 , 95 Cariprazine received FDA approval on September . It is highly metabolized by cytochrome CYP3A4 with the formation of active metabolites and, to a limited extent, by CYP2D6. 96 Cariprazine displays a mean half-life of 2&#;5 days (1.5&#;12.5 mg dose). It generates two clinically relevant metabolites by modification of its urea moiety: desmethyl-cariprazine and didesmethyl-cariprazine, this latter displaying an extended half-life with respect to cariprazine. 97

Lisuride ( 34 , Dopergin, Proclacam, or Revanil, Figure 19 ) is a urea-based ergot-related dopamine agonist used for the therapy of Parkinson&#;s disease (PD). Lisuride also binds the serotonin 5-HT1A, 5-HT2A/2C, and histamine H1 receptors. 92 Studies aimed at examining the metabolism of 14C-lisuride hydrogen maleate in humans and rhesus monkeys demonstrated that 2-keto-3-hydroxy-lisuride was the main metabolic derivative. Parallel metabolic transformations of lisuride were identified, including hydroxylation of the phenyl ring, oxidative N-deethylation, monooxygenation at C2 and C9, and oxidation of C2/C3 and C9/C10 double bonds. 93

Ritonavir ( 33 , Norvir, ABT-538, A-, AbbVie, Inc., Figure 19 ) features a thiazolyl methyl urea substructure. In , it was approved as inhibitor of the HIV protease. 90 Ritonavir displayed an EC 50 of 0.025 μM, plasma half-life of 1.2 h, and bioavailability of 78%. Ritonavir showed an excellent pharmacokinetic profile due to the higher stability of the thiazole moieties toward oxidative metabolism. Ritonavir inhibits CYP3A4 irreversibly binding to the heme iron via the thiazole nitrogen 91 thus increasing plasma concentrations of other CYP3A4 substrate anti-HIV drugs, improving their efficacy.

Boceprevir ( 32 , Victrelis, Merck, Figure 19 ) is a urea containing protease inhibitor useful against hepatitis C virus (HCV). Boceprevir reversibly binds the active site of nonstructural protein 3 (NS3) and displays high potency in the replicon system alone or combined with interferon α&#;2b and ribavirin. 14 Boceprevir is a diastereomeric mixture of two compounds differing in the stereochemical configuration at the cyclobutylmethyl functionality appended to its ketoamide end. In January , Merck announced market withdrawing for boceprevir due to the striking superiority of newer agents (e.g., ledipasvir/sofosbuvir). Oxidative metabolites of boceprevir are formed upon interaction with CYP3A4 and CYP3A5, while the keto-reduced metabolites mostly form upon transformations mediated by aldo-keto reductases AKR1C2 and AKR1C3. Since boceprevir metabolism encompasses two diverse enzymatic pathways, the drug undergoes drug-drug interaction to a lesser extent. 89

Sorafenib ( 25 , Nexavar, Bayer and Onyx Pharmaceuticals, Figure 19 ) is a diaryl urea multikinase inhibitor acting on c-RAF, B-RAF, c-KIT, FLT3, platelet derived growth factor receptor (PDGFR) α and β, and vascular endothelial growth factor receptor (VEGFR) 1, 2, and 3, among others. 12 It was approved in for the therapy of hepatocellular carcinoma and advanced renal cell carcinoma and is under evaluation for acute myeloid leukemia (AML). 13 , 86 Sorafenib is converted by UDP-glucuronosyltransferase 1A9 (UGT1A9) to its glucuronide and by CYP3A4 to its active metabolite sorafenib N-oxide. 87 , 88

Urea substructures are characteristic of several FDA approved drugs as shown in Figure 1 and Figure 19 . Many urea containing compounds are also undergoing clinical development which will be discussed later. In this section, approved urea derivatives for therapeutic applications are highlighted.

6. PROCEDURES FOR THE SYNTHESIS OF UREA DERIVATIVES

The urea functionality is present in drug molecules, agro-chemicals, resins, and dyes. For this reason, a variety of synthetic methodologies for the preparation of urea derivatives have been developed (Scheme 1). The classical approach for the preparation of urea derivatives involves reagents such as phosgene or its derivative, triphosgene. Urea synthesis typically proceeds through an isocyanate intermediate, which upon reaction with a second amine forms the urea derivatives (Scheme 1). Over the years, a series of environmentally friendly phosgene substitutes were developed in order to overcome the hazardous nature of phosgene. In particular, carbonates, N,N&#;-carbonyldiimidazole, 1,1&#;-carbonylbisbenzotriazole, S-methylthiocarbamate, formamides, and chloroformates have been utilized for the synthesis of urea derivatives. Also, Curtius, Lossen, and Hofmann rearrangements have been employed to generate urea derivatives through the isocyanate intermediates.

Scheme 1.

Traditional Methodologies for the Synthesis of Ureas

More recently, carbon monoxide has been utilized as a reliable alternative to phosgene. Accordingly, catalytic oxidative carbonylation employs amines, an oxidant, and carbon monoxide as starting materials to provide ureas. These reactions are appealing in terms of atom economy standards, with the only byproducts being the reduced form of the oxidant. Various transition metal catalysts including Pd, Co, Ni, Ru, Mn, and Au have been employed to afford urea derivatives. However, outcomes varied and often reaction conditions were harsh. As a result, complex mixtures of ureas, oxamides, and formamides were obtained.

6.1. Synthesis of Urea Derivatives Using Phosgene or Phosgene Equivalents.

The reaction of amines with phosgene represents the most traditional methodology for the generation of urea derivatives. This methodology is commonly preferred for the generation of symmetrical ureas, but also unsymmetrical urea derivatives can be prepared efficiently. In general, amines react with phosgene in the presence of a base to provide the desired isocyanate intermediates.119,120 Subsequent reactions of the isocyanates with diverse amine nucleophiles provide N,N-disubstituted or N,N,N&#;-trisubstituted unsymmetrical urea derivatives. This methodology is widely employed in drug discovery and pharmaceutical research since it represents a convenient method to generate urea derivatives.5 A synthesis of a triazole urea derivative containing a β-lactam ring is shown in Scheme 2. Beta-lactam derivative 41 was reacted with phosgene and 1,2,4-triazole (42) to provide triazole urea 43, a potent and selective monoacylglycerol lipase (MAGL) inhibitor.121

Scheme 2.

Formation of Urea-Containing MAGL Inhibitor 43 Using Phosgene

Bis(trichloromethyl)carbonate (46, BTC, or triphosgene) is a crystalline and stable solid, allowing safe handling. For this reason, it has been considered a safer replacement to phosgene.5 However, the vapor pressure is sufficiently high to easily result in toxic concentrations, therefore safety concerns are also associated with its prolonged use.122,123 The use of triphosgene in the synthesis of urea derivative 47, a potent antitrypanosomal agent, is shown in Scheme 3.124 Aniline derivative 44 was reacted with BTC in the presence of Et3N. The resulting intermediate was reacted with amine 45 to provide 47.

Scheme 3.

Formation of the Urea Derivative 47 Using Triphosgene

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