Synthesis of hypermodified adenosine derivatives as selective adenosine A3 receptor ligands (original) (raw)
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New strategies for the synthesis of A3 adenosine receptor antagonists
Bioorganic & Medicinal Chemistry, 2003
New A 3 adenosine receptor antagonists were synthesized and tested at human adenosine receptor subtypes. An advanced synthetic strategy permitted us to obtain a large amount of the key intermediate 5 that was then submitted to alkylation procedures in order to obtain the derivatives 6-8. These compounds were then functionalised into ureas at the 5-position (compounds 9-11, 18 and 19) to evaluate their affinity and selectivity versus hA 3 adenosine receptor subtype; in particular, compounds 18 and 19 displayed a value of affinity of 4.9 and 1.3 nM, respectively. Starting from 5, the synthetic methodologies employed permitted us to perform a rapid and a convenient divergent synthesis. A further improvement allowed the regioselective preparation of the N 8substituted compound 7. This method could be used as an helpful general procedure for the design of novel A 3 adenosine receptor antagonists without the difficulty of separating the N 8 -substituted pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidines from the corresponding N 7 -isomers. #
Journal of Medicinal Chemistry, 2006
Click chemistry' was explored to synthesize two series of 2-(1,2,3-triazolyl) adenosine derivatives (2)(3)(4)(5)(6)(7)(8)(9)(10). Binding affinity at the human A1, A2A and A3ARs (adenosine receptors) and relative efficacy at the A3AR were determined. Some triazol-1-yl analogues showed A3AR affinity in the low nanomolar range, a high ratio of A3/A2A selectivity and a moderate-to-high A3/A1 ratio. The 1,2,3-triazol-4-yl regiomers typically showed decreased A3AR affinity. Sterically demanding groups at the adenine C2 position tended to reduce relative A3AR efficacy. Thus, several 5-OH derivatives appeared to be selective A3AR antagonists, i.e. 10, with 260-fold binding selective in binding in comparison to the A1AR and displaying a characteristic docking mode in an A3AR model. The corresponding 5-ethyluronamide analogues generally showed increased A3AR affinity and behaved as full agonists, i.e. 17, with 910-fold A3/A1 selectivity.
Bioorganic & Medicinal Chemistry Letters, 2006
The highly selective agonists of the A 3 adenosine receptor (AR), Cl-IB-MECA (2-chloro-N 6 -(3iodobenzyl)-5′-N-methylcarboxamidoadenosine) and its 4′-thio analogue, were successfully converted into selective antagonists simply by appending a second N-methyl group on the 5′uronamide position. The 2-chloro-5′-(N,N-dimethyl)uronamido analogues bound to, but did not activate the human A 3 AR, with K i values of 29 nM (4′-O) and 15 (4′-S) nM, showing >100-fold selectivity over A 1 , A 2A , and A 2B ARs. Competitive antagonism was demonstrated by Schild analysis. The 2-(dimethylamino)-5′-(N,N-dimethyl)uronamido substitution also retained A 3 AR selectivity but lowered affinity. thin layer chromatography Antagonists of the A 3 adenosine receptor (AR) are of potential use for clinical targets, including the treatment of glaucoma, allergic conditions, and inflammation. 1 Potent and selective antagonists for the human A 3 AR have recently been synthesized. 2-6 These human A 3 AR antagonists were found to be weak or ineffective at the rat A 3 AR 7,8 and were unsuitable for evaluation in small animal models or for further development as drugs. Thus, A 3 AR antagonists of which the affinity and selectivity are independent of species are sought as drug candidates. In previous studies, it was found that antagonists derived from adenosine analogs, in contrast to nonpurine heterocyclic antagonists, could be species-independent, potent, and selective A 3 AR antagonists. 9
Medicinal Chemistry of the A3 Adenosine Receptor: Agonists, Antagonists, and Receptor Engineering
Handbook of Experimental Pharmacology, 2009
A 3 adenosine receptor (A 3 AR) ligands have been modified to optimize their interaction with the A 3 AR. Most of these modifications have been made to the N 6 and C2 positions of adenine as well as the ribose moiety, and using a combination of these substitutions leads to the most efficacious, selective, and potent ligands. A 3 AR agonists such as IB-MECA and Cl-IB-MECA are now advancing into Phase II clinical trials for treatments targeting diseases such as cancer, arthritis, and psoriasis. Also, a wide number of compounds exerting high potency and selectivity in antagonizing the human (h)A 3 AR have been discovered. These molecules are generally characterized by a notable structural diversity, taking into account that aromatic nitrogencontaining monocyclic (thiazoles and thiadiazoles), bicyclic (isoquinoline, quinozalines, (aza)adenines), tricyclic systems (pyrazoloquinolines, triazoloquinoxalines, pyrazolotriazolopyrimidines, triazolopurines, tricyclic xanthines) and nucleoside derivatives have been identified as potent and selective A 3 AR antagonists. Probably due to the "enigmatic" physiological role of A 3 AR, whose activation may produce opposite effects (for example, concerning tissue protection in inflammatory and cancer cells) and may produce effects that are species dependent, only a few molecules have reached preclinical investigation. Indeed, the most advanced A 3 AR antagonists remain in preclinical testing. Among the antagonists described above, compound OT-7999 is expected to enter clinical trials for the treatment of glaucoma, while several thiazole derivatives are in development as antiallergic, antiasthmatic and/or antiinflammatory drugs.
Journal of Medicinal Chemistry, 2005
A series of ring-constrained (N)-methanocarba-5′-uronamide 2,N 6 -disubstituted adenine nucleosides have been synthesized via Mitsunobu condensation of the nucleobase precursor with a pseudosugar ring containing a 5′-ester functionality. Following appropriate functionalization of the adenine ring, the ester group was converted to the 5′-N-methylamide. The compounds, mainly 2-chloro substituted derivatives, were tested in both binding and functional assays at human adenosine receptors (ARs), and many were found to be highly potent and selective A 3 AR agonists. Selected compounds were compared in binding to the rat A 3 AR to assess their viability for testing in rat disease models. The N 6 -(3-chlorobenzyl) and N 6 -(3-bromobenzyl) analogues displayed K i values at the human A 3 AR of 0.29 and 0.38 nM, respectively. Other subnanomolar affinities were observed for the following N 6 derivatives: 2,5-dichlorobenzyl, 5-iodo-2-methoxybenzyl, trans-2phenyl-1-cyclopropyl, and 2,2-diphenylethyl. Selectivity for the human A 3 AR in comparison to the A 1 AR was (fold): the N 6 -(2,2-diphenylethyl) analogue 34 (1900), the N 6 -(2,5dimethoxybenzyl) analogue 26 (1200), the N 6 -(2,5-dichlorobenzyl) and N 6 -(2-phenyl-1cyclopropyl) analogues 20 and 33 (1000), and the N 6 -(3-substituted benzyl) analogues 17, 18, 28, and 29 (700-900). Typically, even greater selectivity ratios were obtained in comparison with the A 2A and A 2B ARs. The (N)-methanocarba-5′-uronamide analogues were full agonists at the A 3 AR, as indicated by the inhibition of forskolin-stimluated adenylate cyclase at a concentration of 10 µM. The N 6 -(2,2-diphenylethyl) derivative was an A 3 AR agonist in the (N)methanocarba-5′-uronamide series, although it was an antagonist in the ribose series. Thus, many of the previously known groups that enhance A 3 AR affinity in the 9-riboside series, including those that reducing intrinsic efficacy, may be adapted to the (N)-methanocarba nucleoside series of full agonists.
Recent developments in the field of A3 adenosine receptor antagonists
Drug Development Research, 2003
Adenosine is an endogenous modulator of a large variety of physiological functions through the interaction with specific cell membrane G-protein-coupled receptors classified as A 1 , A 2A , A 2B , and A 3 . Activation of A 3 receptors has been shown to stimulate phospholipase C and to inhibit adenylate cyclase. A 3 agonists also cause stimulation of phospholipase D and the release of inflammatory mediators, such as histamine from mast cells, which are responsible for inflammation and hypotension. For these reasons, the clinical use of A 3 adenosine receptors antagonists for the treatment of asthma and inflammatory disease has been suggested. Recent studies also indicated a possible employment of these derivatives as antitumor agents. Different classes of polyheterocyclic compounds have been identified as potent A 3 antagonists. Herein, we report our past and recent results in the development of tricyclic A 3 selective antagonists. The pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine nucleus has especially been investigated by our group. Our interests were focused on the effects of substitution of the phenyl ring of the arylcarbamoyl moiety at N 5 position and of substituents at C 9 and/or at N 8 pyrazole nitrogen. These studies allowed us to obtain a large variety of compounds which showed affinities in the nanomolar range with human A 3 adenosine receptors with a high degree of selectivity vs. all other receptors subtypes. Thanks to the introduction of alkylating groups at p-position of the N 5 -phenylcarbamoyl chain, we succeeded in realizing potent irreversible A 3 adenosine antagonists. Finally, the replacement of the phenyl nucleus of carbamoyl function with a pyridine ring conferred water solubility to the corresponding derivatives, which are also characterized by high levels of A 3 affinity and selectivity. Drug Dev. Res.
Biochemical Pharmacology, 2004
The affinity and efficacy at four subtypes (A 1 , A 2A , A 2B and A 3 ) of human adenosine receptors (ARs) of a wide range of 2-substituted adenosine derivatives were evaluated using radioligand binding assays and a cyclic AMP functional assay in intact CHO cells stably expressing these receptors. Similar to previous studies of the N 6 -position, several 2-substituents were found to be critical structural determinants for the A 3 AR activation. The following adenosine 2-ethers were moderately potent partial agonists (K i , nM): benzyl , 3-chlorobenzyl (72), 2-(3chlorophenyl)ethyl (41), and 2-(2-naphthyl)ethyl (130). The following adenosine 2-ethers were A 3 AR antagonists: 2,2-diphenylethyl, 2-(2-norbornan)ethyl, Rand S-2-phenylbutyl, and 2-(2chlorophenyl)ethyl. 2-(S-2-Phenylbutyloxy)a-denosine as an A 3 AR antagonist right-shifted the concentration-response curve for the inhibition by NECA of cyclic AMP accumulation with a K B value of 212 nM, which is similar to its binding affinity (K i = 175 nM). These 2-substituted adenosine derivatives were generally less potent at the A 1 AR in comparison to the A 3 AR, but fully efficacious, with binding K i values over 100 nM. The 2-phenylethyl moiety resulted in higher A 3 AR affinity (K i in nM) when linked to the 2-position of adenosine through an ether group (54), than when linked through an amine (310) or thioether (1960). 2-[2-(l-Naphthyl)ethyloxy]adenosine (K i = 3.8 nM) was found to be the most potent and selective (>50fold) A 2A agonist in this series. Mixed A 2A /A 3 AR agonists have been identified. Interestingly, although most of these compounds were extremely weak at the A 2B AR, 2-[2-(2naphthyl)ethyloxy]adenosine (EC 50 = 1.4 µM) and 2-[2-(2-thienyl)-ethyloxy]adenosine (EC 50 = 1.8 (M) were found to be relatively potent A 2B agonists, although less potent than NECA (EC 50 = 140 nM).
New base-altered adenosine analogues: Synthesis and affinity at adenosine A1 and A2A receptors
Bioorganic & Medicinal Chemistry Letters, 1997
N(6)-Substituted adenosine analogues containing cyclic hydrazines or chiral hydroxy (ar)alkyl groups, designed to interact with the S2 and S3 receptor subregions, have been synthesized and their binding to the adenosine A1 and A2A receptors have been investigated. Examples of both types of compounds were found to exhibit highly selective binding (Ki in low nM range) to the rat A1 receptor.
Bioorganic & Medicinal Chemistry Letters, 2010
The synthesis of two series of 4 0 -aza-carbocyclic nucleosides are described in which the 4 0 -substituent is either a reversed amide, relative to the carboxamide of NECA, or an N-bonded heterocycle. Using established purine substitution patterns, potent and selective examples of agonists of the human adenosine A 2A receptor have been identified from both series. The propionamides 14-18 and the 4-hydroxymethylpyrazole 32 were determined to be the most potent and selective examples from the 4 0 -reversed amide and 4 0 -N-bonded heterocyclic series, respectively.
Journal of Medicinal Chemistry, 1990
The synthesis and receptor-binding profiles at adenosine receptor subtypes for a series of 2-(arylalkylamino)adenosin-5'-uronamides is described. Halogenated 2-phenethylamino analogues such as 3e show greater than 200-fold selectivity for the A2 receptor subtype on the basis of rat brain receptor binding. The general structure-activity relationship of this series of compounds is discussed both in terms of potency a t A2 receptors as well as receptor subtype selectivity. It is possible to introduce a hydrophilic carboxyalkyl substituent to this series such as in CGS 21680A (3h) and still retain good potency and selectivity for A2 receptors. In addition, functional data in a perfused working rat heart model shows that these compounds possess full agonist properties at A2 receptors with 3h having a greater than 1500-fold separation between A2 (coronary vosadilatory) and A, (negative chronotropic) receptor mediated events.