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Pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines and Structurally Simplified Analogs. Chemistry and SAR Profile as Adenosine Receptor Antagonists
No full textAdenosine was defined as a neuromodulator which exerts its action by interaction with specific G-protein coupled receptor termed adenosine receptors. Adenosine receptors are expressed in several tissues and cells of our body and exist as four different subtypes of these receptors: A1, A2, A2B and A3. In the last years significant efforts were made to obtain highly potent and selective ligands for the four adenosine receptors subtypes. Both agonists and antagonists were used as pharmacological tools to study therapeutic implications of enhancing or blocking the adenosine receptors activity, and some of these compounds have reached clinical phases. The pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines (PTPs) represent one of the several templates designed as adenosine receptor antagonists. A lot of synthetic work was made on this scaffold in order to obtain potent A2 and A3 antagonists. Here were reviewed the synthetic approaches followed by both academia and industry to introduce different substituents at different positions of the PTP nucleus, in particular at the 2, 5, 7, 8 and 9 positions. Nevertheless PTP derivatives are tricyclic compounds with a high molecular weight which exhibit limitations such as poor aqueous solubility and difficult synthetic preparation. With the aim to obtain derivatives with the same potency and selectivity of PTP but with better drug-like properties, researchers made structural simplification of this scaffold. Replacement of the pyrazole or triazole rings of PTP led to the [1,2,4]triazolo[1,5-c]pyrimidine and pyrazolo[3,4- d]pyrimidine derivatives, respectively. Synthetic strategies for these compounds were reported, combined with the SAR profile on the adenosine receptors
Chapter 1: A3 adenosine receptor ligands in the treatment of inflammation and cancer
No full textA3 adenosine receptor is a G protein-coupled receptor belonging to P1 family of purinergic receptors. It is widely distributed in human organs and tissues with various expression levels. In particular, A3 adenosine receptor is highly expressed in several immune cells and cancer cell lines. For this reason its modulation is intensively studied for the involvement in inflammation and cancer. Ligands (agonists and antagonists) presenting high affinity and selectivity for the A3 adenosine receptor are essential for determining the role of such receptor in these pathophysiological conditions and, eventually, for the development of potential drugs for their treatment. In this review we summarize old and new discoveries on therapeutic applications of the A3 adenosine receptor in inflammation and cancer, and highlight the most important agonists and antagonists developed for the A3 adenosine receptor, explicitlythose in clinical trials for the treatment of inflammation and/or cancer
The current status of pharmacotherapy for the treatment of Parkinson's disease: transition from single-target to multitarget therapy
Get PDFParkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons. Motor features such as tremor, rigidity, bradykinesia and postural instability are common traits of PD. Current treatment options provide symptomatic relief to the condition but are unable to reverse disease progression. The conventional single-target therapeutic approach might not always induce the desired effect owing to the multifactorial nature of PD. Hence, multitarget strategies have been proposed to simultaneously target multiple proteins involved in the development of PD. Herein, we provide an overview of the pathogenesis of PD and the current pharmacotherapies. Furthermore, rationales and examples of multitarget approaches that have been tested in preclinical trials for the treatment of PD are also discussed
Simplification of Pyrazolo-triazolo-pyrimidine Nucleus for Searching New Adenosine Receptor Antagonists.
No full textBlockade of adenosine receptors (ARs) lead to a broad variety of effects in several organ systems permitting to consider antagonists for ARs as potential therapeutic targets. Several classes of heterocyclic derivatives have been reported as ARs antagonists with high levels of both affinity and selectivity. [1] In particular, in the last years, the nucleus of pyrazolo-triazolo-pyrimidines as ARs antagonists was deeply investigated. Modulating the substitution at the N5, N7 and N8 positions potent and selective A2A (1) and A3 (2) ARs antagonists have been synthesized.[2,3] Nevertheless this class of compounds, such as other tricyclic structures, showed several problems such as poor water solubility and most importantly tangled synthetic preparation.
On these bases we tried to simplify the nucleus in order to avoid the problems related to this structure. In particular we developed triazolo-triazines [4], triazolopyrimidines and the extremely basic arylstyrenes derivatives. All the obtained results will be summarized
Scaffold decoration at positions 5 and 8 of 1,2,4-triazolo[1,5- c ]pyrimidines to explore the antagonist profiling on adenosine receptors: A preliminary structure-activity relationship study
No full textThe structure-activity relationship (SAR) of new 5,8-disubstituted-1,2,4-triazolo[1,5-c]pyrimidines as adenosine receptors (ARs) antagonists has been explored. All the synthesized compounds show affinity for the hA2A and hA3 ARs depending on the substitution patterns at the 5 and 8 positions. In particular, a free amino group at the 5 position with an ethoxycarbonyl group at the 8 position leads to potent and quite selective hA2A antagonists (compound 12: hA2A AR Ki=3.32 nM; hA1/hA2A=55.6; hA2A/hA3=0.01), whereas the introduction of a methylamino function at the 5 position yields a good binding profile at the hA3 AR (compound 23: hA3 AR Ki=4.14 nM, hA1/hA3=236; hA2A/hA3=25). Through an in silico receptor-driven approach, we have determined the most favorable orientation of the substitutions at the 5 and 8 positions of the 1,2,4-triazolo[1,5-c]pyrimidine (TP) scaffold and, accordingly, we have elucidated the observed SAR
5,7-Disubstituted-[1,2,4]triazolo[1,5-a][1,3,5]triazines as pharmacological tools to explore the antagonist selectivity profiles toward adenosine receptors
Get PDFThe structureeactivity relationship of new 5,7-disubstituted-[1,2,4]triazolo[1,5-a][1,3,5]triazines as adenosine receptors (ARs) antagonists has been explored. The introduction of a benzylamino group at C5 with a free amino group at C7 increases the affinity toward all the ARs subtypes (10: KihA1 1⁄4 94.6 nM; KihA2A 1⁄4 1.11 nM; IC50hA2B 1⁄4 2214 nM; KihA3 1⁄4 30.8 nM). Replacing the free amino group at C7 with a phenylureido moiety yields a potent and quite selective hA2A AR antagonist (14: hA2A AR Ki 1⁄4 1.44 nM; hA1/hA2A 1⁄4 216.0; hA3/hA2A 1⁄4 20.6). This trend diverges from the analysis on the pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine series previously reported. With the help of an in silico receptor-driven approach, we have rationalized these observations and elucidated from a molecular point of view the role of the benzylamino group at C5 in determining affinity toward the hA2A AR
Exploring Directionality of 5-Substitutions in a New Series of 5-Alkyamino-pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine as a Strategy to Design Novel Human A3 Adenosine Receptors Antagonists.
No full textThe activation of A3 adenosine receptors (ARs) is related to various second messenger systems: in particular, they have been shown to stimulate phospholipase C and D and to inhibit adenylyl cyclase.[1] In the rat, the activation of A3 AR results in hypotension through the promotion of the release of inflammatory mediators from mast cells.[2] It has also been suggested that the A3 AR plays an important role in brain ischemia, immunosuppression and cellular growth.[1]
On the basis of these pharmacological observations, many efforts have been made in search of highly selective A3 AR antagonists as potential antiasthmatic, antinflammatory and cerebroprotective agents and for the treatment of glaucoma.[1,3] For this purpose, in the last few years, different classes of heterocyclic derivatives have emerged as A3 AR antagonists.[1]
The structure activity relationship (SAR) of new 5-alkylamino-pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidines as antagonists of the A3 AR was explored with the principal aim to establish the directionality of 5-subtitutions inside the orthosteric binding site of the A3 AR. All the synthesized compounds showed affinity for the hA3 AR from nanomolar to sub-nanomolar range. In particular, the most potent and selective antagonist presents an (S) α-phenylethylamino decoration at the 5 position (Ki hA3 = 0.3 nM). Using an in silico receptor-driven approach, we have determined the most favorable orientation of the substitutions at the 5-position of the pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine scaffold, opening at the possibility to further derivatization directing the N5 position toward the extracellular environment.
[1] Cheong, S.L.; Federico, S.; Venkatesan, G.; Mandel, A.L.; Shao, Y.M.; Moro, S.; Spalluto,G.; Pastorin, G. The A3 adenosine receptor as multifaceted therapeutic target: pharmacology, medicinal chemistry and in silico approaches. Med. Res. Rev. In press, DOI 10.1002/med.20254.
[2] Ramkumar, V.; Stiles, G.L.; Beaven, M.A.; Ali, H. The A3 adenosine receptors is the unique adenosine receptor which facilitates release of allergic mediators in mast cells. J. Biol. Chem. 1993, 268, 16887-16890.
[3] Jacobson, K. A.; Gao, Z. G. Adenosine receptors as therapeutic targets. Nat. Rev. Drug Discov. 2006, 5, 247-264
Pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines to develop functionalized ligands to target adenosine receptors: fluorescent ligands as an example
No full textA series of adenosine receptor antagonists bearing a reactive linker was developed. Functionalization of these derivatives is useful to easily obtain multi-target ligands, receptor probes, drug delivery systems, and diagnostic or theranostic systems. The pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffold was chosen as a pharmacophore for the adenosine receptors. It was substituted at the 5 position with reactive linkers of different lengths. Then, these compounds were used to synthesise probes for the adenosine receptors by functionalization with a fluorescent moiety. Both series of compounds were evaluated for their binding at the four adenosine receptor subtypes. Different affinity and selectivity profiles were observed towards hA1, hA2A and hA3 adenosine receptors. In particular, fluorescent compounds behave as dual hA2A/hA3 ligands. Computational studies suggested different binding modes for developed compounds at the three receptors. Both molecular docking and supervised molecular dynamics (SuMD) simulations confirmed that the preferred binding mode at the single receptor was driven by the substitution present at the 5 position. Obtained results rationalized the compounds' binding profile at the adenosine receptors and pave the way for the development of more potent conjugable and conjugated ligands targeting these membrane receptors
[1,2,4]Triazolo[1,5-c]pyrimidines as adenosine receptor antagonists: Modifications at the 8 position to reach selectivity towards A3 adenosine receptor subtype
Get PDF[1,2,4]Triazolo[1,5-c]pyrimidine is a promising platform to develop adenosine receptor antagonists. Here, we tried to investigate the effect of the substituent at the 8 position of [1,2,4]triazolo[1,5-c]pyrimidine derivatives on affinity and selectivity at the human A3 adenosine receptor subtype. In particular, we have introduced both esters and amides, principally with a benzylic nature. In addition, a small series of 5-substituted [1,2,4]triazolo[1,5-c]pyrimidines was designed in order to complete the structure-activity relationship analysis. Several of these new compounds showed affinity towards human A3 adenosine receptor in the low nanomolar range, with the most potent derivative of the series bringing a 4-ethylbenzylester at the 8 position (compound 18, hA3AR Ki 1⁄4 1.21 nM). Docking studies performed on the synthesized compounds inside models of human A1, A2A and A3 adenosine receptors showed similar binding modes, comparable with the typical crystallographic binding mode of the inverse agonist ZM-241,385
AMINO ACID BASED DENDRIMER PEPTIDE: SYNTHESIS, CHARACTERIZATION AND APPLICATIONS
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