The Identification of the 2-Phenylphthalazin-1(2<i>H</i>)-one Scaffold as a New Decorable Core Skeleton for the Design of Potent and Selective Human A<sub>3</sub> Adenosine Receptor Antagonists

Poli, Daniela; Catarzi, Daniela; Colotta, Vittoria; Varano, Flavia; Filacchioni, Guido; Daniele, Simona; Trincavelli, Maria Letizia; Martini, Claudia; Paoletta, Silvia; Moro, Stefano

doi:10.1021/jm101328n

Cited by 57 publications

(42 citation statements)

References 49 publications

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“…In particular, derivatives form hydrogen bond with the key residue Asn250 (TM6) (3H‐bonds for PHTZ and TQZ, whereas 2H‐bonds for QZ) and a strong π–π interaction between the tri/bicyclic core and Phe168 (ECL2). In addition, several hydrophobic interactions involving the same residues were observed for all scaffolds and these are clearly highlighted by a hydrophobic interaction score between compounds and each amino acid involved in ligand recognition …”

Section: Molecular Modeling On Ha3ar and Its Ligandsmentioning

confidence: 90%

“…f. Other bicyclic scaffolds : A novel and promising scaffold was represented by 2‐phenylphthalazin‐1(2H)‐one, which derives from a molecular simplification of the extensively studied 2‐aryl‐1,2,4‐triazolo[4,3‐a]quinoxalin‐1‐one (TQX, Section ,B.2.c) and the 4‐carboxamido‐quinazoline (QZ) scaffolds. The authors focused their attention on the 4‐position of the nucleus, discovering new potent and selective antagonists active against the A 3 AR subtype (compound 135 , K i hA 3 AR = 0.776 nM) …”

Section: Medicinal Chemistry Of A3ar Ligandsmentioning

confidence: 99%

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The A₃ adenosine receptor as multifaceted therapeutic target: pharmacology, medicinal chemistry, and in silico approaches

Cheong

Federico

Venkatesan

et al. 2011

Medicinal Research Reviews

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Adenosine is an ubiquitous local modulator that regulates various physiological and pathological functions by stimulating four membrane receptors, namely A(1), A(2A), A(2B), and A(3). Among these G protein-coupled receptors, the A(3) subtype is found mainly in the lung, liver, heart, eyes, and brain in our body. It has been associated with cerebroprotection and cardioprotection, as well as modulation of cellular growth upon its selective activation. On the other hand, its inhibition by selective antagonists has been reported to be potentially useful in the treatment of pathological conditions including glaucoma, inflammatory diseases, and cancer. In this review, we focused on the pharmacology and the therapeutic implications of the human (h)A(3) adenosine receptor (AR), together with an overview on the progress of hA(3) AR agonists, antagonists, allosteric modulators, and radioligands, as well as on the recent advances pertaining to the computational approaches (e.g., quantitative structure-activity relationships, homology modeling, molecular docking, and molecular dynamics simulations) applied to the modeling of hA(3) AR and drug design.

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Section: Molecular Modeling On Ha3ar and Its Ligandsmentioning

confidence: 90%

Section: Medicinal Chemistry Of A3ar Ligandsmentioning

confidence: 99%

The A₃ adenosine receptor as multifaceted therapeutic target: pharmacology, medicinal chemistry, and in silico approaches

Cheong

Federico

Venkatesan

et al. 2011

Medicinal Research Reviews

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“…Molecular manipulations by introduction of amide and ureide functional groups at the 4‐position of the phthalazinone ring led to compound 58 (Fig. ) with the best activity profile . Additionally, the 2‐(4‐methyl‐1 H ‐benzo[ d ]imidazol‐2‐yl)‐quinoxaline 59 (Fig.…”

Section: Medicinal Chemistry Of the A3 Adenosine Receptormentioning

confidence: 99%

A₃ Adenosine Receptors as Modulators of Inflammation: From Medicinal Chemistry to Therapy

Jacobson

Merighi

Varani

et al. 2017

Medicinal Research Reviews

125

181

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The A adenosine receptor (A AR) subtype is a novel, promising therapeutic target for inflammatory diseases, such as rheumatoid arthritis (RA) and psoriasis, as well as liver cancer. A AR is coupled to inhibition of adenylyl cyclase and regulation of mitogen-activated protein kinase (MAPK) pathways, leading to modulation of transcription. Furthermore, A AR affects functions of almost all immune cells and the proliferation of cancer cells. Numerous A AR agonists, partial agonists, antagonists, and allosteric modulators have been reported, and their structure-activity relationships (SARs) have been studied culminating in the development of potent and selective molecules with drug-like characteristics. The efficacy of nucleoside agonists may be suppressed to produce antagonists, by structural modification of the ribose moiety. Diverse classes of heterocycles have been discovered as selective A AR blockers, although with large species differences. Thus, as a result of intense basic research efforts, the outlook for development of A AR modulators for human therapeutics is encouraging. Two prototypical selective agonists, N6-(3-Iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA; CF101) and 2-chloro-N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA; CF102), have progressed to advanced clinical trials. They were found safe and well tolerated in all preclinical and human clinical studies and showed promising results, particularly in psoriasis and RA, where the A AR is both a promising therapeutic target and a biologically predictive marker, suggesting a personalized medicine approach. Targeting the A AR may pave the way for safe and efficacious treatments for patient populations affected by inflammatory diseases, cancer, and other conditions.

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“…5AeD) revealed that the ortho (26,29) and meta (27,30) substituted compounds are able to effectively establish additional interactions (mainly hydrogen bonds with geometrically reasonable bond distance and angles) with T270 (7.35), Y271 (7.36), and S267 (7.32) or E170 (EL2) (depending on the specific compound) residues at the hA 1 AR. Interestingly, the para substituted compounds (28, 31) did not establish these interactions (most likely for geometric reasons) on either the hA 1 or hA 2A AR subtypes, according to their lower affinity data.…”

Section: Molecular Modeling Studiesmentioning

confidence: 99%

7-Amino-2-phenylpyrazolo[4,3-d]pyrimidine derivatives: Structural investigations at the 5-position to target human A1 and A2A adenosine receptors. Molecular modeling and pharmacological studies

Squarcialupi

Colotta

Catarzi

et al. 2014

European Journal of Medicinal Chemistry

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The Identification of the 2-Phenylphthalazin-1(2H)-one Scaffold as a New Decorable Core Skeleton for the Design of Potent and Selective Human A₃ Adenosine Receptor Antagonists

Cited by 57 publications

References 49 publications

The A₃ adenosine receptor as multifaceted therapeutic target: pharmacology, medicinal chemistry, and in silico approaches

The A₃ adenosine receptor as multifaceted therapeutic target: pharmacology, medicinal chemistry, and in silico approaches

A₃ Adenosine Receptors as Modulators of Inflammation: From Medicinal Chemistry to Therapy

7-Amino-2-phenylpyrazolo[4,3-d]pyrimidine derivatives: Structural investigations at the 5-position to target human A1 and A2A adenosine receptors. Molecular modeling and pharmacological studies

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The Identification of the 2-Phenylphthalazin-1(2H)-one Scaffold as a New Decorable Core Skeleton for the Design of Potent and Selective Human A3 Adenosine Receptor Antagonists

Cited by 57 publications

References 49 publications

The A3 adenosine receptor as multifaceted therapeutic target: pharmacology, medicinal chemistry, and in silico approaches

The A3 adenosine receptor as multifaceted therapeutic target: pharmacology, medicinal chemistry, and in silico approaches

A3 Adenosine Receptors as Modulators of Inflammation: From Medicinal Chemistry to Therapy

7-Amino-2-phenylpyrazolo[4,3-d]pyrimidine derivatives: Structural investigations at the 5-position to target human A1 and A2A adenosine receptors. Molecular modeling and pharmacological studies

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The Identification of the 2-Phenylphthalazin-1(2H)-one Scaffold as a New Decorable Core Skeleton for the Design of Potent and Selective Human A₃ Adenosine Receptor Antagonists

The A₃ adenosine receptor as multifaceted therapeutic target: pharmacology, medicinal chemistry, and in silico approaches

The A₃ adenosine receptor as multifaceted therapeutic target: pharmacology, medicinal chemistry, and in silico approaches

A₃ Adenosine Receptors as Modulators of Inflammation: From Medicinal Chemistry to Therapy