Pyrazolo-triazolo-pyrimidine Scaffold as a Molecular Passepartout for the Pan-Recognition of Human Adenosine Receptors (original) (raw)
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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.
Bioorganic & Medicinal Chemistry, 2011
In an attempt to study the optimal combination of a phenyl ring at the C 2 -position and different substituents at the N 5 -and N 8 -positions towards the selective modulation of human A 3 adenosine receptors (hA 3 AR), we synthesized a new series of 2-para-(un)substituted-phenyl-pyrazolo-triazolo-pyrimidines bearing either a methyl or phenylethyl at N 8 and chains of variable length at N 5 . Through biological evaluation, it was found that the majority of the compounds had good affinities towards the hA 3 AR in the low nanomolar range. Compound 16 possessed the best hA 3 AR affinity and selectivity profile (K i hA 3 = 1.33 nM; hA 1 /hA 3 = 4880; hA 2A /hA 3 = 1100) in the present series of 2-(substituted)phenylpyrazolo-triazolo-pyrimidine derivatives. In addition to pharmacological characterization, a molecular modeling investigation on these compounds further elucidated the effect of different substituents at the pyrazolo-triazolo-pyrimidine scaffold on affinity and selectivity to hA 3 AR.
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.
Journal of medicinal …, 2003
An enlarged series of pyrazolotriazolopyrimidines previously reported, in preliminary form (Baraldi et al. J. Med. Chem. 1999, 42, 4473-4478), as highly potent and selective human A 3 adenosine receptor antagonists is described. The synthesized compounds showed A 3 adenosine receptor affinity in the sub-nanomolar range and high levels of selectivity evaluated in radioligand binding assays at human A 1 , A 2A , A 2B , and A 3 adenosine receptors. In particular, the effect of the chain at the N 8 pyrazole nitrogen was analyzed. This study allowed us to identify the derivative with the methyl group at the N 8 pyrazole combined with the 4-methoxyphenylcarbamoyl moiety at the N 5 position as the compound with the best binding profile in terms of both affinity and selectivity (hA 3 ) 0.2 nM, hA 1 /hA 3 ) 5485, hA 2A /hA 3 ) 6950, hA 2B /hA 3 ) 1305). All the compounds proved to be full antagonists in a specific functional model where the inhibition of cAMP generation by IB-MECA was measured in membranes of CHO cells stably transfected with the human A 3 receptor. The new compounds are among the most potent and selective A 3 antagonists so far described. The derivatives with higher affinity at human A 3 adenosine receptors proved to be antagonists, in the cAMP assay, capable of inhibiting the effect of IB-MECA with IC 50 values in the nanomolar range, with a trend strictly similar to that observed in the binding assay. Also a molecular modeling study was carried out, with the aim to identify possible pharmacophore maps. In fact, a sterically controlled structure-activity relationship was found for the N 8 pyrazole substituted derivatives, showing a correlation between the calculated molecular volume of pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine derivatives and their experimental K i values. Scheme 1 a a Reagents: (i) NaH, DMF, RX; (ii) HC(OEt)3, reflux; (iii) 2-furoic hydrazide, MeO(CH2)2OH; (iv) Ph2O, 260°C, flash chromatography; (v) HCl, reflux; (vi) NH2CN, 1-methyl-2-pyrrolidone, pTsOH, 140°C. Scheme 2 a a Reagents: (i) 99% HCOOH, 130°C, 48 h.
Journal of Medicinal Chemistry, 2012
A relevant problem of the pyrazolo[4,3-e]-[1,2,4]triazolo [1,5-c]pyrimidine nucleus, an attractive scaffold for the preparation of adenosine receptor antagonists, is the low water solubility. We originally functionalized the C 5 position with a salifiable 4-pyridylcarbamoyl moiety that conferred good water solubility at low pH (<4.0) but poor solubility at physiologic pH, indicative of the dissociation of the pyridinium species. Here we replaced the pyridin-4-yl moiety with a 1-(substituted)piperidin-4-yl ring to exploit the higher basicity of this nucleus and for the the possibility to generate stable, water-soluble salts. The hydrochloride salt of the 1-(cyclohexylmethyl)piperidin-4-yl derivative (10, K i (hA 3 ) = 9.7 nM, IC 50 (hA 3 ) = 30 nM, K i (hA 1 /hA 3 ) = 351, K i (hA 2A /hA 3 ) > 515, IC 50 (hA 2B) > 5 μM) showed a solubility of 8 mg/mL at physiological pH and gave a stable aqueous system suitable for intravenous infusion. Molecular modeling studies were helpful in rationalizing the available structure−activity relationships and the selectivity profile of the new ligands.
Pyrrolo- and pyrazolo-[3,4-e][1,2,4]triazolo[1,5-c]pyrimidines as adenosine receptor antagonists
Bioorganic & Medicinal Chemistry, 2012
The discovery and development of adenosine receptor antagonists have represented for years an attractive field of research from the perspective of identifying new drugs for the treatment of widespread disorders such as inflammation, asthma and Parkinson's disease. The present work can be considered as an extension of our structure-activity relationship studies on the pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine (PTP) nucleus, extensively investigated by us as a useful template, in particular, for the identification of A 2A and A 3 adenosine receptor antagonists. In order to explore the role of the nitrogen at the 7-position, we performed a new synthetic strategy for the preparation of pyrrolo[3,4-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives which can be considered as 7-deaza analogues of the parent PTPs. We also synthesised a novel series of pyrazolo[3,4-e][1,2,4]triazolo[1,5-c]pyrimidines as junction isomers of the reference compounds. In both cases we obtained some examples of potent antagonists (K i in the low nanomolar range) with variable selectivity profiles in relation to the nature of substituents introduced at the C 5 -, N 8 -and/or N 9 -positions. The pyrrolo-triazolo-pyrimidine derivative 9b appeared to be a potent A 3 adenosine receptor antagonist (K i = 10 nM) with good selectivity over hA 1 (74-fold) and hA 2A (20-fold) adenosine receptors combined with low activity at the hA 2B subtype (IC 50 = 906 nM). Moreover, some examples of high-affinity A 1 /A 2A dual antagonists have been identified in both series. This work constitutes a new and important contribution for the comprehension of the interaction between PTPs and adenosine receptors.
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...
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.
International Journal of Medicinal Chemistry, 2011
In the past few decades, medicinal chemistry research towards potent and selective antagonists of human adenosine receptors (namely, A 1 , A 2A , A 2B , and A 3 ) 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]-1,2,4triazolo- [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.
Drugs targeting the four adenosine receptor (AR) subtypes can provide “soft" treatment of various significant diseases. Even for the two experimentally resolved AR subtypes the description of the orthosteric binding area and structure-activity relationships of ligands remains a demanding task due to the high similar amino acids sequence but also the broadness and flexibility of the ARs binding area. The identification of new pharmacophoric moieties and nanomolar leads and the exploration of their binding area with mutagenesis and state-of-the-art computational methods useful also for drug design purposes remains a challenging aim for all ARs. Here, we identified several low nanomolar ligands and potent competitive antagonists against A1R / A3R, containing the novel pyrazolo[3,4-c]pyridine pharmacophore for ARs, from a screen of an in-house library of only 52 compounds, originally designed for anti-proliferative activity. We identified L2-L10, A15, A17 with 3-aryl, 7-anilino and...