Derivatives of 4-Amino-6-hydroxy-2-mercaptopyrimidine as Novel, Potent, and Selective A3 Adenosine Receptor Antagonists (original) (raw)
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Bioorganic & Medicinal Chemistry, 2006
pyrimidinediones have previously been found to bind to adenosine A 1 and A 2A receptors in micromolar concentrations. The present study was aimed at studying the structure-activity relationships of this class of compounds in more detail. Most of the investigated compounds were provided with polar substituents, such as ethoxycarbonyl groups and basic amino functions, in order to improve their water-solubility. The compounds were synthesized starting from 6-amino-1,3-dimethyluracil via different reaction sequences involving (cyano)acetylation, Vilsmeier formylation, or reaction with diethyl ethoxymethylenemalonate (EMME). The most potent and selective compound of the present series was 6-carbethoxy-1,2,3,4-tetrahydro-1,3-dimethyl-5-(2-naphthylmethyl)aminopyrido[2,3-d]pyrimidine-2,4-dione (11c) with a K i value of 5 nM at rat and 25 nM at human A 1 receptors. The compound was more than 60-fold selective versus A 3 and more than 300-fold selective versus A 2A receptors. It showed an over 300-fold improvement with respect to the lead compound. In GTPcS binding studies at membranes of Chinese hamster ovary cells recombinantly expressing the human adenosine A 1 receptor, 11c behaved as an antagonist with inverse agonistic activity. A regioisomer of 11c, 6-carbethoxy-1,2,3,4-tetrahydro-1,3-dimethyl-7-(2-naphthylmethyl)aminopyrido[2,3-d]pyrimidine-2,4-dione (7a) in which the 2-naphthylmethylamino substituent at position 5 of 11c was moved to the 7-position, was a relatively potent (K i = 226 nM) and selective (>20-fold) A 3 ligand. In the series of compounds lacking an electron-withdrawing ethoxycarbonyl or cyano substituent in the 6-position, compounds with high affinity for adenosine A 2A receptors were identified, such as 1,2,3,4-tetrahydro-1,3-dimethyl-5-(1-naphthyl)aminopyrido[2,3-d]pyrimidine-2,4-dione 16b (K i human A 2A = 81.3 nM, K i human A 1 = 153 nM, and K i human A 3 > 10,000 nM).
Archiv der Pharmazie, 2013
A series of novel pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives 5 was prepared from 2-amino-3cyano-4-trifluoromethyl-6-phenylpyridine 1 in two steps via formation of iminoether 3 followed by reaction with different aroylhydrazides 4. Representative products 5 were evaluated for their affinity towards all four subtypes of human adenosine receptors. Compounds 2-(3-fluorophenyl)-8-phenyl-10-(trifluoromethyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (5b), 2-(furan-2-yl)-8-phenyl-10-(trifluoromethyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (5d), and 2-(furan-2-yl)-5-methyl-8-phenyl-10-(trifluoromethyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (5j) showed high affinity for the A 3 receptors, with K i values of 8.1, 10.4, and 12.1 nM, respectively, and were >1000-fold selective versus all other adenosine receptor subtypes.
Bioorganic & Medicinal Chemistry, 2014
In the present study, a molecular simplification approach was employed to design novel bicyclic pyrazolo[3,4-d]pyrimidine (PP) derivatives from tricyclic pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidines (PTP) as promising human A 3 adenosine receptor (hA 3 AR) antagonists. All the target compounds were synthesized using novel and efficient synthetic schemes and the structure-activity relationship studies of these PPs were explored through the synthesis of a series of PTP analogues with various substituents. Substituents with different lipophilicity and steric hindrance (e.g., alkyl and aryl-alkyl) functions were introduced at N 2 position of the pyrazole ring, while acyl groups with different electronic properties were introduced at C 6 position of the bicyclic nucleus to probe both electronic and positional effects. Most of the synthesized derivatives of the PP series presented good affinity at the hA 3 AR, as indicated by the low micromolar range of K i values and among them, compound 63 with N 2 neopentyl substituents showed most potent hA 3 AR affinity with K i value of 0.9 lM and high selectivity (hA 1 AR/hA 3 AR = >111 & hA 2A-AR/hA 3 AR = >111) towards other adenosine receptor subtypes. Interestingly, small isopropyl groups at N 2 position displayed high affinity at another receptor subtype (hA 2A AR, e.g., compound 55, with K i hA 2A-AR = 0.8 lM), while they were less favorable at the hA 3 AR. Molecular docking analysis was also performed to predict the possible binding mode of target compounds inside the hA 3 AR and hA 2A AR. Overall, PP derivatives represent promising starting points for new AR antagonists.
Bioorganic & Medicinal Chemistry Letters, 2011
A ligand-based pharmacophore was obtained for a new series of 2-unsubstituted and 2-(para-substituted)phenyl-pyrazolo-triazolo-pyrimidines as potent human A 3 adenosine receptor antagonists. Through comparative molecular field analysis-based quantitative structure-activity relationship studies, structural features at the N 5 -, N 8 -and C 2 -positions of the tricyclic nucleus were deeply investigated, with emphasis given to the unprecedentedly explored C 2 -position. The resulting model showed good correlation and predictability (r 2 = 0.936; q 2 = 0.703; r 2 pred ¼ 0:663). Overall, the contribution of steric effect was found relatively more predominant for the optimal interaction of these antagonists to the human A 3 receptor.
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. #
European Journal of Medicinal Chemistry, 1999
Starting from the appropriate azides (4-chlorobenzyl-, 2-thiophenemethyl-, 2-fluorobenzyl-, and 4-fluorobenzylazides) in which the variation of the substituent is at the basis of the four series of derivatives (a-d), the 7-aminosubstituted 1,2,3-triazolo[4,5-d]pyrimidines 4 were prepared by a well known synthetic route. The biological activity of compounds 4 was expected on the basis of the presence of particular substituents on N(7), and these substituents were introduced by the reaction of the 7 lactamic carbonyl function, present on precursors 3, with cycloalkyl-, aralkyl-and arylamines. Radioligand binding assays at bovine brain adenosine A 1 and A 2A receptors showed that some compounds possessed a high affinity and selectivity for the A 1 receptor subtype. Furthermore, biological results indicated that the p-chlorobenzyl substituent lowered receptor binding, compared with the previously prepared benzyl and 2-chlorobenzyl derivatives, suggesting certain particular steric requirements of the lipophilic region which interacts with the benzyl substituent. The thiophenemethyl substituent conferred more activity than the benzyl one. The presence of a fluorine atom on the benzyl group determined a high affinity, especially when it was in the ortho position. Compounds 4c.1 (R = 2-fluorobenzyl, R≠ = cyclopentyl, Ki = 10.5 nM), 4c.2 (R = 2-fluorobenzyl, R≠ = cyclohexyl, Ki = 19.5 nM) and 4d.1 (R = 4-fluorobenzyl, R≠ = cyclopentyl, Ki = 26 nM) were the most active for A 1 receptors. © 1999 Éditions scientifiques et médicales Elsevier SAS 1,2,3-triazoles / 1,2,3-triazolo[4,5-d]pyrimidines / A 1 -adenosine and A 2A -adenosine receptor antagonists
Journal of Medicinal Chemistry, 1998
Three series of several 1,2,3-triazolo [4,5-d]pyrimidine derivatives bearing various amino substituents at the 7 position and one of three lipophilic substituents at the 3 position (benzyl, phenethyl, or 2-chlorobenzyl) were prepared starting from the corresponding 7-chloro compounds, by nucleophilic substitution by the appropriate amine. Radioligand binding assays at bovine brain adenosine A 1 and A 2A receptors showed that some compounds possessed a high affinity and selectivity for the A 1 receptor subtype. In particular the biological results suggested the compounds bearing cycloalkylamino (cyclopentyl-and cyclohexylamino) or aralkylamino (R-methylbenzyl-and 1-methyl-2-phenylethylamino or amphetamino) substituents at the 7 position were the most active derivatives. The best lipophilic substituent at the 3 position was the 2-chlorobenzyl (A 1 affinity K i < 50 nM) followed by the benzyl and then the phenethyl groups. This pattern of structure-activity relationship (SAR) was similar to that previously reported for analogous 1,2,3-triazolopyridazino derivatives except for the compounds bearing substituted aromatic amines which presented a generalized and strong decrease of the A 1 receptor affinity. These facts allowed us to attribute to these molecules a binding mode within the A 1 adenosine receptor analogous to that of the corresponding triazolopyridazines.
European journal of medicinal chemistry, 2015
An efficient synthetic procedure was adopted to synthesize a series of new molecules containing the pyrazolo[3,4-d]pyrimidine (PP) scaffold, which have been evaluated as promising human adenosine receptor (AR) antagonists. The effect of substitutions at the N(2), C(4) and C(6) positions of PPs on the affinity and selectivity towards the adenosine receptors were explored. Most of the pyrazolo[3,4-d]pyrimidine-4-carboxylates displayed from moderate to good affinity at the human A3AR (hA3AR), as indicated by the low micromolar range of Ki values (Ki hA3AR = 0.7-34 μM). In particular, compounds 60 and 62 displayed good affinity at the hA3AR (60, Ki hA3AR = 2.2 μM and 62, Ki hA3AR = 2.9 μM) and selectivity towards the other AR subtypes (60, >46-fold selective and 62, >34-fold selective, respectively). In view of these results, these novel PP analogues were docked both in the crystallographic structure of the hA2AAR and in a homology model of the hA3AR in order to support the struct...
Purinergic Signalling, 2008
In the last few years, many efforts have been made to search for potent and selective human A 3 adenosine antagonists. In particular, one of the most promising human A 3 adenosine receptor antagonists is represented by the pyrazolo-triazolo-pyrimidine family. This class of compounds has been strongly investigated from the point of view of structure-activity relationships. In particular, it has been observed that fundamental requisites for having both potency and selectivity at the human A 3 adenosine receptors are the presence of a small substituent at the N 8 position and an unsubstitued phenyl carbamoyl moiety at the N 5 position. In this study, we report the role of the N 5 -bond type on the affinity and selectivity at the four adenosine receptor subtypes. The observed structureactivity relationships of this class of antagonists are also exhaustively rationalized using the recently published ligand-based homology modeling approach.