Further studies on pyrazolo[1',5':1,6]pyrimido[4,5-d]pyridazin-4(3H)-ones as potent and selective human A1 adenosine receptor antagonists (original) (raw)
Related papers
2010
A series of pyrazolo[1 0 ,5 0 :1,6]pyrimido [4,5-d]pyridazin-4(3H)-ones was synthesized and tested in radioligand binding assays to determine their affinities for the human adenosine A 1 , A 2A , A 2B and A 3 receptors. Results indicated that this scaffold is appropriate for adenosine receptor subtype A 1 ligands and that the best arranged groups around this scaffold are 3-and 4-pyridinyl at position 1, benzyl at position 3, hydrogen at position 6 and 3-thienyl or phenyl at position 9. The most interesting compounds showed K i for A1 in the nanomolar range and an appreciable selectivity for other receptor subtypes.
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.
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.
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.
Journal of Medicinal Chemistry, 2009
The paper describes a new class of human (h) A(3) adenosine receptor antagonists, the 2-arylpyrido[2,3-e]-1,2,4-triazolo[4,3-a]pyrazin-1-one derivatives (PTP), either 4-oxo (1-6, series A) or 4-amino-substituted (7-20, series B). In both series A and B, substituents able to act as hydrogen bond acceptors (OMe, OH, F, COOEt) were inserted on the 2-phenyl ring. In series B, cycloalkyl and acyl residues were introduced on the 4-amino group. Some of the new derivatives showed high hA(3) AR affinities (K(i) < 50 nM) and selectivities vs both hA(1) and hA(2A) receptors. The selected 4-benzoylamino-2-(4-methoxyphenyl)pyrido[2,3-e]-1,2,4-triazolo[4,3-a]pyrazin-1-one (18), tested in an in vitro rat model of cerebral ischemia, proved to be effective in preventing the failure of synaptic activity induced by oxygen and glucose deprivation in the hippocampus. Molecular docking of this new class of hA(3) AR antagonists was carried out to depict their hypothetical binding mode to our refined model of hA(3) receptor.
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.
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.
Bioorganic & Medicinal Chemistry Letters, 2007
Antagonism of the adenosine A 2A receptor offers great promise in the treatment of Parkinson's disease. Employing the known pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine A 2A antagonist SCH 58261 as a starting point, we identified the potent and selective (vs. A1) antagonist 11 h, orally active in the rat haloperidol-induced catalepsy model. We further optimized this lead to the methoxyethoxyethyl ether 12a (SCH 420814), which shows broad selectivity, good pharmacokinetic properties, and excellent in vivo activity.