Pyrazolo Derivatives as Potent Adenosine Receptor Antagonists: An Overview on the Structure-Activity Relationships

Cheong, Siew Lee; Venkatesan, Gopalakrishnan; Paira, Priyankar; Jothibasu, Ramasamy; Mandel, Alexander Laurence; Federico, Stephanie; Spalluto, Giampiero; Pastorin, Giorgia

doi:https://doi.org/10.1155/2011/480652

International Journal of Medicinal Chemistry

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Review Article | Open Access

Volume 2011 | Article ID 480652 | https://doi.org/10.1155/2011/480652

Pyrazolo Derivatives as Potent Adenosine Receptor Antagonists: An Overview on the Structure-Activity Relationships

Siew Lee Cheong,¹Gopalakrishnan Venkatesan,¹Priyankar Paira,¹Ramasamy Jothibasu,¹Alexander Laurence Mandel,¹Stephanie Federico,²Giampiero Spalluto,²and Giorgia Pastorin¹

Academic Editor: Rosaria Volpini

Received02 Nov 2010

Accepted10 Feb 2011

Published07 Apr 2011

Abstract

In the past few decades, medicinal chemistry research towards potent and selective antagonists of human adenosine receptors (namely, A₁, A_2A, A_2B, and A₃) has been evolving rapidly. These antagonists are deemed therapeutically beneficial in several pathological conditions including neurological and renal disorders, cancer, inflammation, and glaucoma. Up to this point, many classes of compounds have been successfully synthesized and identified as potent human adenosine receptor antagonists. In this paper, an overview of the structure-activity relationship (SAR) profiles of promising nonxanthine pyrazolo derivatives is reported and discussed. We have emphasized the SAR for some representative structures such as pyrazolo-[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidines; pyrazolo-[3,4-c] or -[4,3-c]quinolines; pyrazolo-[4,3-d]pyrimidinones; pyrazolo-[3,4-d]pyrimidines and pyrazolo-[1,5-a]pyridines. This overview not only clarifies the structural requirements deemed essential for affinity towards individual adenosine receptor subtypes, but it also sheds light on the rational design and optimization of existing structural templates to allow us to conceive new, more potent adenosine receptor antagonists.

1. Introduction

Adenosine is an endogenous nucleoside that mediates a wide range of physiological responses through interaction with specific adenosine receptors (ARs), which are G-protein-coupled receptors (GPCRs) comprising the characteristic seven transmembrane domains connected by three extracellular and three intracellular loops. There are four basic types of ARs that have been cloned and pharmacologically characterized, namely, A₁, A_2A, A_2B, and A₃ ARs [1]. Each of these ARs is associated with its own distinct biochemical pathways. Typically, the activation of A₁ and A₃ receptors mediates adenylyl cyclase inhibition through an interaction with G_i protein, followed by a subsequent decrease in the level of cyclic adenosine monophosphate (cAMP); conversely, the A_2A and A_2B receptors stimulate the adenylyl cyclase activity via the G_s protein thereby increasing the level of cAMP [2]. In addition, other signaling pathways involving phospholipases C and D, and Ca²⁺ and mitogen-activated protein kinases (MAPK) have also been described [1]. Pharmacologically, the inhibition of A₁ receptors has led to implications in the renal system disorders through regulation of diuresis and neurological disorders such as Alzheimer’s disease [3, 4]; on the other hand, A₃ receptor antagonists are primarily related to the treatment of glaucoma, renal protection, inflammatory disorders like asthma, as well as cancer [5–7]. Studies have also found that A_2A receptor antagonists can reverse Parkinsonian motor deficits in preclinical models of Parkinson’s disease, and they do so without inducing or exacerbating dyskinesias in nonhuman primate models [8, 9]. As for the A_2B receptor, its antagonists seem to be suitable for the treatment of certain forms of inflammatory processes such as asthma via modulation of mast cell degranulation [10, 11].

In the last 15 years, intensive efforts in medicinal chemistry to design and synthesize new AR antagonists have led to the discovery of potent and selective ligands (with either agonistic or antagonistic properties) for the A₁, A_2A, A_2B, and A₃ ARs. These new derivatives have resulted in a better understanding of the pathophysiological role of these receptors; more precisely, among the AR antagonists, several different types of xanthine-derived and nonxanthine-based polyheterocyclic structures have been identified as potent AR antagonists. Some of them are shown to possess good affinity exclusively towards a particular AR subtype with concomitant improvements in their selectivity profiles. On the other hand, some scaffolds demonstrate good binding affinity across more than one AR subtype, with relatively lower selectivity profile. Among these diverse classes of compounds, nonxanthine pyrazolo derivatives have been reported to show good potency towards ARs, together with a broad range of selectivity. The aim of this review is to briefly summarize the structure-activity relationship profiles of various nonxanthine derivatives containing the pyrazole moiety as AR antagonists to the A₁, A_2A, A_2B, and A₃ receptor subtypes.

2. Pyrazolo Derivatives as Potent AR Antagonists

In general, nonxanthine AR antagonists are represented by polyheterocyclic derivatives which are categorized as monocyclic, bicyclic, or tricyclic structures [12]. In this review, we emphasized the structure-activity relationships for some of the representative nonxanthine pyrazolo derivatives (i.e., derivatives with a fused pyrazole ring in their respective core nuclei), which have been identified as potent AR antagonists at the A₁, A_2A, A_2B, or A₃ receptor subtypes. These derivatives are pyrazolo-[4,3-e]1,2,4-triazolo-[1,5-c]pyrimidines, pyrazolo-[3,4-c] or -[4,3-c] quinolines, pyrazolo-[4,3-d]pyrimidinones, pyrazolo-[3,4-d]pyrimidines, and pyrazolo-[1,5-a]pyridines. The binding data of the most representative AR antagonists belonging to these series are reported in Table 1.

2.1. Pyrazolo-[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidine

2.1.1. A_2A AR Antagonists

The pyrazolo-triazolo-pyrimidine derivatives were first described as AR antagonists by Gatta and coworkers [13], who identified a compound named 8FB-PTP (1 in Figure 1), which demonstrated good binding to the A_2A AR but lacked selectivity towards the A₁ receptor subtype. Structure-affinity relationship studies showed that the free amino group at 5-position and the effect of the substituents on the pyrazole ring seemed important for both high affinity and selectivity for the A_2A AR subtype. From further studies, substitutions at the 7-position were shown to improve the selectivity for the A_2A receptor while the same substitutions at the 8-position increased affinity to the A₁ and A_2A receptors with low levels of selectivity, as indicated by the N⁷-n-butyl (2) and the N⁸-n-butyl (3) derivatives [14, 15]. This again indicated that the presence of a chain (preferably a long (ar)alkyl one) at the N⁷ position seemed essential for both affinity and selectivity for the A_2A receptors.

(a)

(b)

In fact, two selected compounds named SCH 63390 (4) and SCH 58261 (5) proved to be the most potent and selective A_2A AR antagonists ever reported, both in rat and human models [15–17]. The latter was further developed into an A_2A antagonist radioligand, [³H]SCH 58261 (5a) with a value of about 1 nM. Further studies have suggested that it could be a useful tool for characterization of A_2A receptor subtypes in platelets, autoradiography assays, and labeling of striatal A_2A receptors for studying A_2A receptor occupancy of various antagonists [18, 50, 51]. Nevertheless, this class of compounds presents a significant problem because of poor water solubility. To overcome this drawback, several polar moieties on the side chain of the pyrazole nucleus have been introduced. In particular, the introduction of a hydroxyl function at the para position of the phenyl ring of compounds (4) and (5) led to derivatives (5-amino-7-[3-(4-hydroxyphenyl)propyl]-2-(2-furyl)pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine) (6) and (5-amino-7-[β-(4-hydroxyphenyl)ethyl]-2-(2-furyl)pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine) (7), which not only showed a better hydrophilic character but also a significant increase of both affinity and selectivity for the A_2A AR subtype, suggesting that most probably, a hydrogen bond is involved in receptor recognition via this part of the ligand [16].

To understand the nature of such a hypothetical hydrogen bond, compound SCH 442416 (8) was synthesized. This derivative showed even higher affinity and selectivity for the A_2A receptor, thus representing a suitable candidate for positron emission tomography (PET) studies in its ¹¹C-labeled form [19]. Moreover, it was developed into novel fluorescent tracer MRS5346 (9), which was conjugated to the fluorescent dye Alexa Fluor-488. It has a value of 16.5 ± 4.7 nM and could be used in fluorescence polarization competition binding experiments as well as high-throughput screening [20]. On top of that, this SCH 442416 derivative also confirmed the role of a hydrogen bond via the pyrazolo side chain. Nonetheless, the introduction of oxygenated groups could not be considered sufficient to confer water solubility. Hence, carboxylic (10) and sulfonic (11) moieties were introduced, and such structural modifications (the sulfonic moiety in particular) improved water solubility. However, in some cases, a loss of affinity with respect to reference compounds (6, 7) for the A_2A AR was observed. On the other hand, the introduction of an amino group at the para position of the phenyl ring (12) improved both affinity and selectivity towards the A_2Areceptor, although with low water solubility [17]. Despite these observations, it was found that the N⁷ derivative (such as compound 5) was totally inactive to the human A_2B and A₃ receptors. The N⁸ regioisomer (13), however, showed a slight affinity profile for these two receptor subtypes [21, 22].

A recent series of pyrazolo-triazolo-pyrimidine derivatives was obtained by modifying the phenylethyl substituent of 5 with substituted phenylpiperazine ethyl groups [23]. Introduction of fluorine atoms in the phenyl ring (14) enhanced the affinity to subnanomolar values and the compounds displayed potent oral activity, but their solubilities still remained poor. Further introduction of ether substituents led to derivatives with high affinities and selectivities for A_2A receptors and improvements in water solubility. In particular, one of these compounds (SCH 420814, Privadenant, 15) exhibited high affinity for both rat and human A_2A receptors, with values of 2.5 and 1.1 nM, respectively. In addition, the compound was very selective for human A_2A receptors over A₁, A_2B, and A₃ receptors. Interestingly, the compound did not show significant binding against a panel of 59 unrelated receptors, enzymes and ion channels. Privadenant is now in Phase II Clinical Trials for the treatment of dyskinesia in Parkinson's disease.

2.1.2. A_2B AR Antagonists

The binding data obtained from parallel studies on A_2A receptor antagonists have indicated that the N⁵-unsubstituted pyrazolo-triazolo-pyrimidine derivatives (13 in Figure 1, 16 in Figure 2) possessed high affinity to the human A_2B receptors but completely lacked selectivity. Subsequently, introduction of a polar γ-amino-butyryl amide (17) at the N⁵-position decreased affinity towards the A_2B receptors but was found to be slightly selective against the A_2A subtype [24]. An improvement of this class of compounds was further achieved by an optimized pattern of substitutions at the N⁵- and N⁸-positions. In fact, in parallel studies on human A₃ receptor antagonists (to be elaborated in the following section), it was observed that replacement of the phenylcarbamoyl moiety at the N⁵-position with a phenylacetyl group (compound 18) produced a decrease in affinity to the human A₃ AR and a retention or improvement towards the A_2B subtype. A combination of a naphthyl acetyl moiety at the N⁵-position and a phenyl propyl group (characteristic of A_2A antagonists) at the N⁸ position led to a compound (19), which was found to be quite potent and selective towards the A_2B ARs [25]. These findings indicated that bulky substituents at both the N⁵- and N⁸-positions could lead to potent and selective A_2B AR antagonists, thus suggesting the presence of a larger pocket in the receptor binding site.

2.1.3. A₃ AR Antagonists

The optimization approach to obtain potent A₃ AR antagonists in the series of pyrazolo-triazolo-pyrimidines was a hybrid molecule between a human A_2A receptor antagonist [15, 16] and an agonist of the A₃ subtype [52, 53]. The tricyclic scaffold of a known human A_2A antagonist was substituted at the N⁵ position with an aryl carbamoyl moiety. Specifically, this para-methoxyphenyl was demonstrated to be optimal for A₃ affinity when introduced at the N⁶-position of the A₃ agonist NECA (as represented by compound 20; Figure 3). Such rational design led to compound 21, which is one of the most potent and selective human A₃ AR antagonists [21]. Subsequent collation of binding data and molecular modeling studies indicated that small substituents, such as a methyl group at the N⁸-position, the phenyl ring on the N⁵-carbamoyl moiety, and a furyl ring at 2-position, were important (although not crucial, as indicated in the following paragraphs) for A₃ affinity (e.g., compound 23) [22, 27–29]. Only small substituents at the para position of the phenyl ring, including fluoro (F), chloro (Cl), and methoxy (OCH₃) were tolerated. At the meta-position, only hydrogen was tolerated, while the ortho-position could be substituted by a chlorine atom. Introduction of an allyl chain at N⁸-position, followed by reduction with tritium afforded [³H]MRE-3008-F20 (22), which was the first selective and tritiated human A₃ receptor antagonist radioligand [26]. It showed a value of 0.8 nM and exhibited ca. 25% of nonspecific binding at that concentration. Since its discovery, it has been used for the identification of A₃ receptors on various cells, including Jurkat T cells, HL60 cells, and human neutrophils [54, 55]. Later, the N⁵-phenyl ring of the tricyclic scaffold was substituted with a pyridinium salt, as represented by compound 24, which not only showed good solubility (15 mM) but also significantly improved hA₃ affinity [30]. In previous studies, substitution of the N⁵-pyridine moiety with various N⁵-heteroaryl rings resulted in a general loss of hA₃ affinity and selectivity [28].

Substitution at position C² of the tricyclic system has not been deeply explored, being essentially limited to a furyl group. The furan ring had been considered to be an essential structural requirement for the binding of antagonists to all of the AR subtypes, since its removal from the tricyclic system was associated with an irreversible loss of affinity and selectivity, regardless of the receptor under investigation. In fact, Baraldi and coworkers [31] found that the substitution of the furan ring in PTPs with phenyl (25) or alkoxyphenyl rings led to a loss of affinity to A_2A, A_2B, and A₃ receptors, while the A₁ subtype in some cases displayed a high nanomolar binding profile. Similarly, the functionalization of the furan ring with polar substituents led to completely inactive derivatives, clearly indicating that an unsubstituted furan ring at the C² position played a fundamental role in ligand-receptor recognition [31]. Notably, in most cases, substitution at the pyrazole ring occurred at the N⁷-rather than at the N⁸-position. Recently, a new series of 2-aryl pyrazolo-triazolo-pyrimidines was reported by Cheong et al., in which the previously conserved furan at C² was substituted with a 2-aryl ring while substitutions on pyrazole ring were maintained at the N⁸-position [32]. Such bioisosteric replacement at C² resulted in improved human A₃ affinity and remarkably enhanced selectivity over other AR subtypes. The para substituents at the 2-phenyl ring were generally well tolerated, except for a para-nitro group, which caused detrimental effects on hA₃ affinity. Particularly, the para-OCH₃ and para-F groups conferred better affinities and selectivities towards the hA₃ receptor. The most potent compound in this series (26) had a methyl group at the N⁸-position, a phenylacetamide at the N⁵-position, and a phenyl ring at the C²-position. Interestingly, Okamura et al. also described a series of pyrazolo-triazolo-pyrimidine analogues with a para-(un)substituted-phenyl ring and an alkyl chain at the C²- and C⁵-positions, respectively, that was shown to possess good hA₃ affinity. The selectivity against other AR subtypes was significantly improved in this group of derivatives, especially when a para-substituted-2-phenyl ring was present (as illustrated by compounds 27, 28) [6, 33]. It was also observed that the introduction of a substituent (e.g., NHCH₂CH₃ (29) and SCH₃) at the C⁹-position, induced a loss of both affinity and selectivity towards the A₃ receptor. It was postulated that the introduction of these substituents caused a repulsive effect due to steric hindrance, which hampered the interaction with the binding site of the A₃ AR [31].

2.2. Pyrazolo-[3,4-c] or -[4,3-c]quinolines

2.2.1. A₃ AR Antagonists

The series of pyrazoloquinolin-4-ones and pyrazolo[3,4-c]quinolines, 4-oxo and 4-amino substituted, shared a similar central scaffold as that of the triazoloquinoxalinones (30, 31) [34–38], and they were found to be potent and selective A₃ AR antagonists (Figure 4) [39, 40]. The substituent on the appended 2-phenyl ring was crucial to modulate A₃ affinity while a nuclear (e.g., oxo group) or extranuclear (e.g., amide group) C=O proton acceptor at the 4-position gave rise to potent and selective A₃ antagonists. At the 2-position, the presence of 4-Cl, 4-OCH₃, 4-CH₃, and 3-CH₃ on the 2-phenyl ring resulted in enhancement of A₃ affinities in both the 4-ones (32) and 4-amino (33) series. Conversely, the substituents on the 2-phenyl ring of the 4-amido derivatives generally maintained but did not ameliorate the high A₃ affinities in comparison with the 2-phenyl parent derivatives. At the 4-position, the introduction of 4-benzoylamido (34), 4-phenylacetylamido, and 4-carbamoyl residues resulted in improved human A₃ affinities and selectivities, confirming the importance of the C=O group at this position towards A₃ receptor-ligand interaction. Among the 4-amido derivatives, the 4-acetylamido group showed lower human A₃ affinity in comparison to the other bulkier 4-acyl moieties, thus implying not only the presence of a roomy receptor pocket around this region, but also the importance of hydrophobic interactions between the 4-substituents and the receptor site. Another series of 2-phenyl-2,5-dihydro-pyrazolo[4,3-c]quinolin-4-ones, which are the structural isomers of the parent 2-arylpyrazolo[3,4-c]quinoline derivatives, have also been reported by Baraldi et al. [41]. Some of the synthesized compounds showed good A₃ affinities (nanomolar ranges) and excellent selectivities. Particularly, the substitution of methyl, methoxy, or chlorine at the para-position of the 2-phenyl ring, together with the presence of a 4-oxo functionality gave good A₃ affinity and selectivity (35).

2.3. Pyrazolo-[4,3-d]pyrimidinones

2.3.1. A₃ AR Antagonists

The pyrazolo-[4,3-d]pyrimidin-7-ones, which were a molecular simplification of the tricyclic scaffold of pyrazolo-[3,4-c]quinolin-4-one, have recently been shown to possess good affinity and selectivity profiles for the hA₃ receptor [42]. According to the structure-activity relationship (SAR) analysis, both the substituents at the C⁵- and N²-positions of the bicyclic nucleus were crucial for the human A₃ affinity and selectivity. The concomitant presence of small alkyl chains, such as methyl group at the C⁵-position and a para-methoxy-substituted phenyl ring at the N² position (as demonstrated by compound 36 in Figure 5) gave rise to the most potent and selective A₃ AR antagonist in this series of derivatives.

2.4. Pyrazolo-[3,4-d]pyrimidines

2.4.1. A₁ AR Antagonists

A series of pyrazolo-[3,4-d]pyrimidines was identified that contains novel A₁ AR antagonists [43]. The lead compound, 4,6-Bis[α-carbamoylethyl)thio]-1-phenylpyrazolo-[3,4-d]pyrimidine (37 in Figure 6), served as a starting template for the optimization of A₁ affinity and selectivity in this series of compounds. 1-phenyl-pyrazolo-[3,4-d]pyrimidine was modified at C⁴ with mercapto, methylthio, and amino groups in order to investigate the hydrogen-bonding and steric tolerance at this position [44]. At C⁶, thioesters containing distal amides with varying lengths of linear and branched alkyl groups extending from the α-carbon were evaluated for steric and hydrophobic tolerance [44]. From the binding data at A₁ receptor, it was found that the simultaneous presence of an amino at C⁴ and α-butyl side chain at C⁶ gave rise to the most potent compound of the series (38); the least potent compound contained a mercapto and an α-isopropyl side chain at C⁴ and C⁶, respectively. These observations suggested that the superiority of the C⁴-amino group was most likely due to a hydrogen-bonding interaction with the receptor binding sites. Although a C⁴-methylthio group was less preferable than the amino species, its presence was still tolerable, thus indicating the existence of a hydrophobic pocket in the A₁ binding site able to accommodate the methyl group. As for the C⁶ position, the increase in length of the linear carbon side chain (from ethyl to butyl) was favorably tolerated at the A₁ receptor for each C⁴-substituent. Similarly, the hydrophobic tolerance at C⁶ position seemed crucial for the A₁ binding affinity as well. In an attempt to test for the hypothesis mentioned above, a methyl-amino and an α-butyl side chain were concurrently introduced at the C⁴ and C⁶ positions, respectively [44]. Accordingly, the derivative 39 displayed improved A₁ affinity and increased A₁ selectivity, which further supported the proposed structural requirements at both the C⁴ and C⁶ positions.

2.4.2. A_2A AR Antagonists

Pyrazolo-[3,4-d]pyrimidines were also explored by Gillespie and collaborators as A_2A AR antagonists [45]. In particular, the 4-(furan-2-yl)pyrazolo-[3,4-d]pyrimidine (compound 40 in Figure 7) was identified as a starting point for further investigation. It showed a good affinity for the A_2A receptor subtype and was 13-fold more selective over A₁. The following introduction of 1-phenyl substitution (41) increased potency at A_2A while either incorporation of heteroatoms or ring saturation did not improve affinity significantly. Extension of spatial linker between the phenyl ring and pyrazole by more than one methylene group was found to provide an hA_2A affinity profile similar to the 1-phenyl derivative. Furthermore, subsequent substitution on the meta-position of phenyl ring with electron-rich and deficient groups was tolerated, with the 3-chlorobenzyl derivative (42) demonstrating the best hA_2A affinity and selectivity in the series. Moreover, compounds 40–42 have also shown in vivo activity in a mouse haloperidol-induced hypolocomotion model of Parkinson’s disease. Due to the fact that the 4-(furan-2-yl) moiety in this series of compounds could be easily converted into reactive species under oxidative metabolism, further studies were undertaken to replace such group with other nonfuran-containing heterocycles. Unfortunately, the resulting compounds have showed reduced affinity for the A_2A receptor.

2.4.3. A₃ AR Antagonists

Pyrazolo-[3,4-d]pyrimidines represent a novel series of bicyclic scaffold-derived A₃ antagonists [46] isosterically related to the imidazole-[1,2-a][1,3,5]triazine (43; Figure 8), which have shown a certain degree of binding affinity at both A₁and A₃ receptors [56]. Such pyrazolo-pyrimidine analogues displayed improved A₃ affinity and selectivity profiles in comparison to the parent imidazole-triazines. From the binding affinity results, it was suggested that the 6-phenyl substituent at the bicyclic scaffold was a key pharmacophoric element for recognition at the ARs, since its removal led to poor affinity to all the ARs. Besides that, small alkyl groups at the N²-position, such as a methyl moiety were found to be more favourable than bulky groups for conferring good human A₃ affinity. The introduction of N⁴-acyl substituents generally resulted in improved human A₃ affinity relative to unsubstituted derivatives. In particular, the presence of a methyl group at N², together with para-methoxy benzoyl substituent at N⁴ (44) dramatically increased the potency and selectivity to the A₃ AR. Compound 44 was subsequently tested on human glioma U87MG cells, and it was able to counteract the proliferation of glioma cells mediated by A₃ AR agonists Cl-IB-MECA and IB-MECA through the inhibition of A₃ AR agonist-mediated ERK 1/2 activation. This finding implied that this class of derivatives might represent promising lead compounds for the development of adjuvants for glioma chemotherapy [46].

2.5. Pyrazolo-[1,5-a]pyridines

2.5.1. A₁ AR Antagonists

Akahane and coworkers reported a series of pyrazolo-[1,5-a]pyridine derivatives as potent and selective A₁ AR antagonists. FK453 (45 in Figure 9) [47] and FK838 (46) [48] were the typical examples of such derivatives, and they also showed diuretic activity both in vivo and in vitro. Nevertheless, there were some limitations in these two compounds. For FK453, photochemical trans-cis isomerization at the acryloyl amide moiety and low water solubility (11.9 μg/mL) were two main problems in this type of structure. In FK838, photochemical stability was achieved through the substitution of the acryloyl amide with a pyridazinone ring while water solubility (10 mg/mL) was enhanced by the introduction of the butyric acid group. Nevertheless, this derivative had lower binding affinity and poorer selectivity for A₁ receptor than FK453. Subsequently, further structural modifications to FK838 led to the synthesis of FR166124 (47) [49], which is the most potent and selective A₁ AR antagonist of this series, and it shows high water solubility (>200 mg/mL). In fact, it was designed based on the hypothesis that the high affinity and selectivity of FK453 for the A₁ receptor was due to the presence of the (2R)-2-(2-hydroxyethyl)piperidine ring of the acryloyl amide as a conformationally limiting factor. The pyridazinone ring of FK838 was maintained in the structure of FR166124, with the introduction of a ring structure joining the C³ and C⁴ positions of the butyric acid group to limit possible conformations. Overall, the close resemblance of X-ray crystal structures of FR166124 and FK453 to each other, together with the experimental binding assay data, suggested that the presence of a double bond in the cyclohexenyl acetic acid group was essential for high selectivity to the A₁ receptor, with good A₁ affinity and water solubility.

3. Conclusion

Pyrazolo-containing polyheterocyclic scaffolds have given rise to a group of potent and selective antagonists for the A₁, A_2A, A_2B, and A₃ AR subtypes. An overview of the structure-activity relationships of each class of derivatives not only clarifies the structural requirements deemed essential for the affinity towards the individual AR subtypes, but it also lends insight into the rational design and optimization of existing structural templates to obtain other new, potent AR antagonists.

Abbreviations

AR(s):	adenosine receptor(s)
cAMP:	cyclic adenosine monophosphate
Cl-IB-MECA:	2-chloro-N⁶-(3-iodobenzyl)-5′-N-methylcarboxamidoadenosine
ERK 1/2:	extracellular signal-regulated kinase
8FB-PTP:	5-amino-8-(4-fluorobenzyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine
FK453:	2-phenylpyrazolo[1,5-a]pyridine-3-((2R)-2-(2-hydroxyethyl)piperidyl)acryloylamides
FK838:	3-(2-butyric acid-3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine
FR166124:	3-(2-cyclohexenyl acetic acid-3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine
GPCR:	G protein-coupled receptor
[³H]MRE-3008-F20:	[³H]-5-N-(4-methoxyphenylcarbamoyl)amino-8-propyl-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine
IB-MECA:	N⁶-(3-iodobenzyl)-5′- N-methylcarboxamidoadenosine
MAPK:	mitogen-activated protein kinase
MRS5346:	5-((2-(2-(4-(3-(5-amino-2-(furan-2-yl)-7H-pyrazolo[4,3-e][1, 2, 4]triazolo[1,5-c]pyrimidin-7-yl)propyl)phenoxy)acetamido)ethyl)-carbamoyl)-2-(6-amino-3-iminio-4,5-disulfonato-3H-xanthen-9-yl)benzoate
NECA:	N-ethylcarboxamidoadenosine
PET:	positron emission tomography
SCH 63390:	5-amino-7-(3-phenyl propyl)-2-(2-furyl)pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine
SCH 58261:	5-amino-7-(β-phenylethyl)-2-(2-furyl)pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine
SCH 442416:	5-amino-7-[3-(4-methoxyphenyl)propyl]-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine
SCH 420814:	5-amino-7-{[(2-(4-methoxyethoxyphenyl)piperazin-1-yl]ethyl}-2-(2-furyl)-pyrazolo [4,3-e]1,2,4-triazolo[1,5-c]pyrimidine.

Acknowledgments

This paper was supported by the National Medical Research Council, Singapore (Grant no. NMRC/NIG/0020/2008) and the National University of Singapore (FRC Grant no. R-148-000-129-112).

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Copyright © 2011 Siew Lee Cheong et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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International Journal of Medicinal Chemistry

Pyrazolo Derivatives as Potent Adenosine Receptor Antagonists: An Overview on the Structure-Activity Relationships

Abstract

1. Introduction

2. Pyrazolo Derivatives as Potent AR Antagonists

2.1. Pyrazolo-[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidine

2.1.1. A2A AR Antagonists

2.1.2. A2B AR Antagonists

2.1.3. A3 AR Antagonists

2.2. Pyrazolo-[3,4-c] or -[4,3-c]quinolines

2.2.1. A3 AR Antagonists

2.3. Pyrazolo-[4,3-d]pyrimidinones

2.3.1. A3 AR Antagonists

2.4. Pyrazolo-[3,4-d]pyrimidines

2.4.1. A1 AR Antagonists

2.4.2. A2A AR Antagonists

2.4.3. A3 AR Antagonists

2.5. Pyrazolo-[1,5-a]pyridines

2.5.1. A1 AR Antagonists

3. Conclusion

Abbreviations

Acknowledgments

References

Copyright

2.1.1. A_2A AR Antagonists

2.1.2. A_2B AR Antagonists

2.1.3. A₃ AR Antagonists

2.2.1. A₃ AR Antagonists

2.3.1. A₃ AR Antagonists

2.4.1. A₁ AR Antagonists

2.4.2. A_2A AR Antagonists

2.4.3. A₃ AR Antagonists

2.5.1. A₁ AR Antagonists