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Pier Giovanni Baraldi - One of the best experts on this subject based on the ideXlab platform.
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Novel 1,3-Dipropyl-8-(3-benzimidazol-2-yl-methoxy-1-methylpyrazol-5-yl)xanthines as Potent and Selective A2B Adenosine Receptor Antagonists
2016Co-Authors: Pier Giovanni Baraldi, Stefania Baraldi, Giulia Saponaro, Delia Preti, Romeo Romagnoli, Laura Piccagli, Andrea Cavalli, Maurizio Recanatini, Allan R. Moorman, Abdel Naser ZaidAbstract:Molecular modeling studies, including the comparative molecular field analysis (CoMFA) method, on 52 Antagonists of the A2B Adenosine Receptor with known biological activity were performed to identify the three-dimensional features responsible for A2B Adenosine Receptor antagonist activity. On the basis of these and previous results on the potent antagonist effect of 8-pyrazolyl-xanthines at human A2BAR, a new series of compounds was synthesized and evaluated in binding studies against the human A1, A2A, A3, and A2BARs. A remarkable improvement in selectivity with respect to the previous series, maintaining the potency at human A2B Receptor, was achieved, as exemplified by the 8-[3-(4-chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl-methoxy)-1-methyl-1H-pyrazol-5-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione derivative 66: Ki A2B = 9.4 nM, IC50 hA2B = 26 nM hA1/hA2B = 269, hA2A/hA2B > 106, hA3/hA2B >106. This study also led to the identification of a series of pyrazole-xanthine compounds with a simplified structure, exemplified by 8-(3-hydroxy-1-methyl-1H-pyrazol-5-yl)-xanthine 80 displaying very high affinity at A2BAR with good selectivity over AR subtypes (Ki = 4.0 nM, IC50 hA2B = 20 nM hA1/hA2B = 183, hA2A,hA3/hA2B > 250)
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One-Pot Reaction To Obtain N,N′-Disubstituted Guanidines of Pyrazolo[4,3‑e][1,2,4]triazolo[1,5‑c]pyrimidine Scaffold as Human A3 Adenosine Receptor Antagonists
2015Co-Authors: Pier Giovanni Baraldi, Stefania Baraldi, Giulia Saponaro, Romeo Romagnoli, Mojgan Aghazadeh Tabrizi, Fabrizio Vincenzi, Pier Andrea Borea, Emanuela Ruggiero, Katia VaraniAbstract:In this paper we describe an extension SAR study of pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine nucleus as A3AR antagonist. Our initial aim was to replace the phenylcarbamoyl moiety at the 5 position of PTP nucleus with a thiourea functionality to evaluate the contribution of new structural modification against the A3AR. The synthesized 12–25 were not characterized by the predicted side chain but by a 1,3-disubstituted guanidine and are shown to be interesting A3AR Antagonists
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novel 1 3 dipropyl 8 3 benzimidazol 2 yl methoxy 1 methylpyrazol 5 yl xanthines as potent and selective a2b Adenosine Receptor Antagonists
Journal of Medicinal Chemistry, 2012Co-Authors: Pier Giovanni Baraldi, Stefania Baraldi, Giulia Saponaro, Delia Preti, Romeo Romagnoli, Laura Piccagli, Andrea Cavalli, Maurizio Recanatini, Allan R. Moorman, Abdel Naser ZaidAbstract:Molecular modeling studies, including the comparative molecular field analysis (CoMFA) method, on 52 Antagonists of the A2B Adenosine Receptor with known biological activity were performed to identify the three-dimensional features responsible for A2B Adenosine Receptor antagonist activity. On the basis of these and previous results on the potent antagonist effect of 8-pyrazolyl-xanthines at human A2BAR, a new series of compounds was synthesized and evaluated in binding studies against the human A1, A2A, A3, and A2BARs. A remarkable improvement in selectivity with respect to the previous series, maintaining the potency at human A2B Receptor, was achieved, as exemplified by the 8-[3-(4-chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl-methoxy)-1-methyl-1H-pyrazol-5-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione derivative 66: Ki A2B = 9.4 nM, IC50 hA2B = 26 nM hA1/hA2B = 269, hA2A/hA2B > 106, hA3/hA2B >106. This study also led to the identification of a series of pyrazole-xanthine compounds with a simplified s...
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design synthesis and biological evaluation of new 8 heterocyclic xanthine derivatives as highly potent and selective human a2b Adenosine Receptor Antagonists
Journal of Medicinal Chemistry, 2004Co-Authors: Pier Giovanni Baraldi, Delia Preti, Romeo Romagnoli, Allan R. Moorman, Mojgan Aghazadeh Tabrizi, Andrea Bovero, Francesca Fruttarolo, Naser Abdel Zaid, Katia Varani, Stefania GessiAbstract:Here we report the synthesis of 8-heterocycle-substituted xanthines as potent and selective A(2B) Adenosine Receptor Antagonists. The structure-activity relationships (SAR) of the xanthines synthesized in binding to recombinant human A(2B) Adenosine Receptors (ARs) in HEK-293 cells (HEK-A(2B)) and at other AR subtypes were explored. The synthesized compounds showed A(2B) Adenosine Receptor affinity in the nanomolar range and good levels of selectivity evaluated in radioligand binding assays at human (h) A(1), A(2A), A(2B), and A(3) ARs. We introduced several heterocycles, such as pyrazole, isoxazole, pyridine, and pyridazine, at the 8-position of the xanthine nucleus and we have also investigated different spacers (substituted acetamide, oxyacetamide, and urea moieties) on the heterocycle introduced. Various groups at the 3- and 4-positions of phenylacetamide moiety were studied. This study allowed us to identify the derivatives 2-(3,4-dimethoxyphenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide (29b, MRE2028F20) [K(i)(hA(2B)) = 38 nM, K(i)(hA(1),hA(2A),hA(3)) >1000 nM], N-benzo[1,3]dioxol-5-yl-2-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yloxy]acetamide (62b, MRE2029F20) [K(i)(hA(2B)) = 5.5 nM, K(i)(hA(1),hA(2A),hA(3)) > 1000 nM], and N-(3,4-dimethoxyphenyl)-2-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yloxy]acetamide (72b, MRE2030F20) [K(i)(hA(2B) = 12 nM, K(i)(hA(1),hA(2A), hA(3)) > 1000 nM], which showed high affinity at the A(2B) Receptor subtype and very good selectivity vs the other ARs. Substitution of the acetamide with an urea moiety afforded bioisosteric xanthines with good affinity and selectivity comparable to the acetamide derivatives. Substitution at the para-position of a 4-benzyloxy group of the phenylacetamido chain enhanced affinity at the A(2B) Receptor [compound 30b (K(i)(hA(2B)) = 13 nM) vs compound 21b (K(i)(hA(2B) = 56 nM)] but did not favor selectivity. The derivatives with higher affinity at human A(2B) AR proved to be Antagonists, in the cyclic AMP assay, capable of inhibiting the stimulatory effect of NECA (100 nM) with IC(50) values in the nanomolar range, a trend similar to that observed in the binding assay (62b, IC(50) = 38 nM; 72b, IC(50) = 46 nM). In conclusion, the 8-pyrazolo-1,3-dipropyl-1H-purine-2,6-dione derivatives described herein represent a new family of selective Antagonists for the Adenosine A(2B) Receptor.
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design synthesis and biological evaluation of a second generation of pyrazolo 4 3 e 1 2 4 triazolo 1 5 c pyrimidines as potent and selective a2a Adenosine Receptor Antagonists
Journal of Medicinal Chemistry, 1998Co-Authors: Pier Giovanni Baraldi, Katia Varani, Giampiero Spalluto, Barbara Cacciari, Manuela Bergonzoni, S Dionisotti, Ennio Ongini, P A BoreaAbstract:New A2A Adenosine Receptor Antagonists in the series of pyrazolo[4, 3-e]-1,2,4-triazolo[1,5-c]pyrimidines, bearing oxygenated substituents on the phenylalkyl chains on the 7-position, have been synthesized. The compounds were tested in binding and functional assays to evaluate affinity, potency, and selectivity for rat A2A compared to rat A1 and human A3 Receptor subtypes. The most interesting compounds (5d,e,h) were tested also in binding to human A1 and A2A Adenosine Receptors. They showed very good affinity (Ki = 0.94 nM for compound 5h) and interesting selectivity with respect to both rA1 and hA3 (compound 5h: rA1/rA2A = 787, hA3/rA2A > 10 000). These important findings make this new series of compounds the first really selective for A2A Adenosine Receptors. Thermodynamic parameters were evaluated; all the tested compounds displayed an enthalpy-driven binding as expected for Antagonists. Moreover, compound 5h showed a negative entropy value. The highly negative enthalpic and entropic contributions could mean that 5h fits very well in the binding site where, probably, an electrostatic interaction is present associated to a scarce solvent reorganization around the Receptor binding site. These compounds deserve to be further developed to assess their potential for treatment of neurodegenerative disorders such as Parkinson's disease.
Christa E Muller - One of the best experts on this subject based on the ideXlab platform.
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a2b Adenosine Receptor Antagonists with picomolar potency
Journal of Medicinal Chemistry, 2019Co-Authors: Jie Jiang, Jorg Hockemeyer, Catharina Julia Seel, Ahmed Temirak, Vigneshwaran Namasivayam, Antonella Arridu, Jakub Schabikowski, Younis Baqi, Sonja Hinz, Christa E MullerAbstract:The A2B Adenosine Receptor (A2BAR) was proposed as a novel target for the (immuno)therapy of cancer since A2BAR blockade results in antiproliferative, antiangiogenic, antimetastatic, and immunostimulatory effects. In this study, we explored the structure-activity relationships of xanthin-8-yl-benzenesulfonamides mainly by introducing a variety of linkers and substituents attached to the sulfonamide residue. A new, convergent strategy was established, which facilitated the synthesis of the target compounds. Many of the new compounds exhibited subnanomolar affinity for the A2BAR combined with high selectivity. Functional groups were introduced, which will allow the attachment of dyes and other reporter groups. 8-(4-((4-(4-Bromophenyl)piperazin-1-yl)sulfonyl)phenyl)-1-propylxanthine (34, PSB-1901) was the most potent A2B-antagonist (Ki 0.0835 nM, KB 0.0598 nM, human A2BAR) with >10 000-fold selectivity versus all other AR subtypes. It was similarly potent and selective at the mouse A2BAR, making it a promisi...
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past present and future of a2a Adenosine Receptor Antagonists in the therapy of parkinson s disease
Pharmacology & Therapeutics, 2011Co-Authors: Marie Therese Armentero, Sergi Ferre, Christa E Muller, Annalisa Pinna, Jose L Lanciego, Rafael FrancoAbstract:Several selective Antagonists for Adenosine A2A Receptors (A2AR) are currently under evaluation in clinical trials (phases I to III) to treat Parkinson's disease, and they will probably soon reach the market. The usefulness of these Antagonists has been deduced from studies demonstrating functional interactions between dopamine D2 and Adenosine A2A Receptors in the basal ganglia. At present it is believed that A2AR Antagonists can be used in combination with the dopamine precursor L-DOPA to minimize the motor symptoms of Parkinson's patients. However, a considerable body of data indicates that in addition to ameliorating motor symptoms, Adenosine A2AR Antagonists may also prevent neurodegeneration. Despite these promising indications, one further issue must be considered in order to develop fully optimized antiparkinsonian drug therapy, namely the existence of (hetero)dimers/oligomers of G protein-coupled Receptors, a topic that is currently the focus of intense debate within the scientific community. Dopamine D2 Receptors (D2Rs) expressed in the striatum are known to form heteromers with A2A Adenosine Receptors. Thus, the development of heteromer-specific A2A Receptor Antagonists represents a promising strategy for the identification of more selective and safer drugs.
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xanthines as Adenosine Receptor Antagonists
Handbook of experimental pharmacology, 2011Co-Authors: Christa E Muller, Kenneth A. JacobsonAbstract:The natural plant alkaloids caffeine and theophylline were the first Adenosine Receptor (AR) Antagonists described in the literature. They exhibit micromolar affinities and are non-selective. A large number of derivatives and analogues were subsequently synthesized and evaluated as AR Antagonists. Very potent Antagonists have thus been developed with selectivity for each of the four AR subtypes.
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synthesis and preliminary evaluation of new 1 and 3 1 2 hydroxy 3 phenoxypropyl xanthines from 2 amino 2 oxazolines as potential a1 and a2a Adenosine Receptor Antagonists
Bioorganic & Medicinal Chemistry, 2006Co-Authors: Stephane Massip, Christa E Muller, Jean Guillon, Daniela C G Bertarelli, Jeanjacques Bosc, Jeanmichel Leger, Svenja Lacher, Cecile Bontemps, Thibaut Dupont, Christian JarryAbstract:The development of potent and selective Adenosine Receptor ligands as potential drugs is an active area of research. Xanthines are one of the most important classes of Adenosine Receptor Antagonists and have been widely developed in terms of affinity and selectivity for Adenosine Receptors. We recently developed new original pathways for the synthesis of xanthine analogues starting from 5-substituted-2-amino-2-oxazoline 5 as a synthon. These procedures allowed us to selectively introduce a large, functionalized and β-adrenergic 2-hydroxy-3-phenoxypropyl pharmacophore at the 1- and 3-position of the xanthine moiety which allowed further structural modifications. In this study, we present a new synthetic access to racemic xanthine derivatives 1 – 4 from 5 , and their evaluation as Adenosine A 1 , A 2A and A 3 Receptor ligands in radioligand binding studies. The 2-hydroxy-3-phenoxypropyl moiety was well tolerated in the 3-position of the xanthine core, while its introduction in the 1-position of the xanthine moiety led to a large decrease in Adenosine Receptor affinity. 1,7-Dimethyl-3-[1-(2-chloro-3-phenoxypropyl)]-8-(3,4,5-trimethoxystyryl)xanthine ( 2n ) was the most potent and selective A 2A antagonist of the present series ( K i = 44 nM, ≫200-fold selective vs A 1 ). 1-Propyl-3-[1-(2-hydroxy-3-phenoxypropyl)]-8-noradamantylxanthine ( 3f ) was identified as a potent ( K i A 1 = 21 nM) and highly selective (≫350-fold vs A 2A and A 3 Receptor) Adenosine A 1 Receptor antagonist.
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water soluble phosphate prodrugs of 1 propargyl 8 styrylxanthine derivatives a2a selective Adenosine Receptor Antagonists
Journal of Medicinal Chemistry, 2000Co-Authors: Roland Sauer, Karl-norbert Klotz, Juris Maurinsh, Ulrike Reith, Friederike Fulle, Christa E MullerAbstract:Water-soluble prodrugs of potent, A2A-selective Adenosine Receptor (AR) Antagonists were prepared. 8-(m-Bromostyryl)-3,7-dimethyl-1-propargylxanthine (BS-DMPX, 11) and the analogous 8-(m-methoxystyryl)xanthine derivative (MS-DMPX, 5b) were used as starting points. It was found that polar functional groups suitable for the attachment of a prodrug moiety were tolerated on the styryl ring and even better on the 3-substituent. 8-(m-Hydroxystyryl)-DMPX (7) and 3-(3-hydroxypropyl)-8-(m-methoxystyryl)-1-propargylxanthine (5e, MSX-2) were the most potent and A2A-selective compounds and were selected for prodrug formation. For the preparation of 5e a new ring-closure method was applied. Treatment of 6-amino-1-(3-hydroxypropyl)-5-(m-methoxycinnamoylamino)-3-propargyluracil with hexamethyldisilazane at high temperature resulted in higher yields of the target xanthine than the standard ring-closure procedure using sodium hydroxide. Phosphate prodrugs were prepared by classical phosphorylation using phosphorus oxychlo...
Rao Kalla - One of the best experts on this subject based on the ideXlab platform.
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progress in the discovery of selective high affinity a2b Adenosine Receptor Antagonists as clinical candidates
Purinergic Signalling, 2009Co-Authors: Rao Kalla, Jeff ZablockiAbstract:The selective, high affinity A2B Adenosine Receptor (AdoR) Antagonists that were synthesized by several research groups should aid in determining the role of the A2B AdoR in inflammatory diseases like asthma or rheumatoid arthritis (RA) and angiogenic diseases like diabetic retinopathy or cancer. CV Therapeutics scientists discovered the selective, high affinity A2B AdoR antagonist 10, a 8-(4-pyrazolyl)-xanthine derivative [CVT-6883, Ki(hA2B) = 22 nM; Ki(hA1) = 1,940 nM; Ki(hA2A) = 3,280; and Ki(hA3) = 1,070 nM] that has favorable pharmacokinetic (PK) properties (t 1/2 = 4 h and F > 35% rat). Compound 10 demonstrated functional antagonism at the A2B AdoR (KB = 6 nM) and efficacy in a mouse model of asthma. In two phase 1 clinical trials, CVT-6883 was found to be safe, well tolerated, and suitable for once daily dosing. A second compound 20, 8-(5-pyrazolyl)-xanthine, has been nominated for development from Baraldi’s group in conjunction with King Pharmaceuticals that has favorable A2B AdoR affinity and selectivity [Ki(hA2B) = 5.5 nM; Ki(hA1) > 1,000 nM; Ki(hA2A) > 1,000; and Ki(hA3) > 1,000 nM], and it has been demonstrated to be a functional antagonist. A third compound 32, a 2-aminopyrimidine, from the Almirall group has high A2B AdoR affinity and selectivity [Ki(hA2B) = 17 nM; Ki(hA1) > 1,000 nM; Ki(hA2A) > 2,500; and Ki(hA3) > 1,000 nM], and 32 has been moved into preclinical safety testing. Since three highly selective, high affinity A2B AdoR Antagonists have been nominated for development with 10 (CVT-6883) being the furthest along in the development process, the role of the A2B AdoR in various disease states will soon be established.
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selective high affinity a2b Adenosine Receptor Antagonists n 1 monosubstituted 8 pyrazol 4 yl xanthines
Bioorganic & Medicinal Chemistry Letters, 2008Co-Authors: Rao Kalla, Elfatih Elzein, Thao Perry, Dewan Zeng, Art Gimbel, Ming Yang, Jeff ZablockiAbstract:A series of N-1 monosubstituted 8-pyrazolyl xanthines have been synthesized and evaluated for their affinity for the Adenosine Receptors (AdoRs). We have discovered two compounds 18 (CVT-7124) and 28 (CVT-6694) that display good affinity for the A2B AdoR (Ki = 6 nM and 7 nM, respectively) and greater selectivity for the human A1, A2A, and A3 AdoRs (>1000-, >830-, and >1500-fold; >850-, >700-, and >1280-fold, respectively). CVT-6694 has been shown to block the release of interleukin-6 and monocyte chemotactic protein-1 from bronchial smooth muscle cells (BSMC), a process believed to be promoted by activation of A2B AdoR.
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novel 1 3 disubstituted 8 1 benzyl 1h pyrazol 4 yl xanthines high affinity and selective a2b Adenosine Receptor Antagonists
Journal of Medicinal Chemistry, 2006Co-Authors: Rao Kalla, Elfatih Elzein, Thao Perry, Venkata P Palle, Vaibhav Varkhedkar, Arthur Gimbel, Tennig Maa, Dewan Zeng, Jeff ZablockiAbstract:Adenosine has been suggested to induce bronchial hyperresponsiveness in asthmatics, which is believed to be an A(2B) Adenosine Receptor (AdoR) mediated pathway. We hypothesize that a selective, high-affinity A(2B) AdoR antagonist may provide therapeutic benefit in the treatment of asthma. In an attempt to identify a high-affinity, selective antagonist for the A(2B) AdoR, we synthesized 8-(C-4-pyrazolyl) xanthines. Compound 22, 8-(1H-pyrazol-4-yl)-1,3-dipropyl xanthine, is a N-1 unsubstituted pyrazole derivative that has favorable binding affinity (K(i) = 9 nM) for the A(2B) AdoR, but it is only 2-fold selective versus the A(1) AdoR. Introduction of a benzyl group at the N-1-pyrazole position of 22 resulted in 19, which had moderate selectivity. The initial focus of the SAR study was on the preparation of substituted benzyl derivatives of 19 because the corresponding phenyl, phenethyl, and phenpropyl derivatives showed a decrease in A(2B) AdoR affinity and selectivity relative to 19. The preferred substitution on the phenyl ring of 19 contains an electron-withdrawing group, specifically F or CF(3) at the m-position, as in 33 and 36 respectively, increases the selectivity while retaining the affinity for the A(2B) AdoR. Exploring disubstitutions on the phenyl ring of derivatives 33 and36 led to the 2-chloro-5-trifluoromethylphenyl derivative 50, which retained the A(2B) AdoR affinity but enhanced the selectivity relative to 36. After optimization of the substitution on the 8-pyrazole xanthine, 1,3-disubstitution of the xanthine core was explored with methyl, ethyl, butyl, and isobutyl groups. In comparison to the corresponding dipropyl analogues, the smaller 1,3-dialkyl groups (methyl and ethyl) increased the A(2B) AdoR binding selectivity of the xanthine derivatives while retaining the affinity. However, the larger 1,3-dialkyl groups (isobutyl and butyl) resulted in a decrease in both A(2B) AdoR affinity and selectivity. This final SAR optimization led to the discovery of 1,3-dimethyl derivative 60, 8-(1-(3-(trifluoromethyl) benzyl)-1H-pyrazol-4-yl)-1,3-dimethyl xanthine, a high-affinity (K(i) = 1 nM) A(2B) AdoR antagonist with high selectivity (990-, 690-, and 1,000-) for the human A(1), A(2A,) and A(3) AdoRs.
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novel 1 3 dipropyl 8 1 heteroarylmethyl 1h pyrazol 4 yl xanthine derivatives as high affinity and selective a2b Adenosine Receptor Antagonists
Bioorganic & Medicinal Chemistry Letters, 2006Co-Authors: Elfatih Elzein, Rao Kalla, Thao Perry, Venkata P Palle, Vaibhav Varkhedkar, Dewan Zeng, Art Gimbel, Eric Q Parkhill, David Lustig, Kwan LeungAbstract:Abstract A series of new 1,3-dipropyl-8-(1-heteroarylmethyl-1 H -pyrazol-4-yl)-xanthine derivatives as A 2B -AdoR Antagonists have been synthesized and evaluated for their binding affinities for the A 2B , A 1 , A 2A , and A 3 -AdoRs. 8-(1-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)-1 H -pyrazol-4-yl)-1,3-dipropyl-1 H -purine-2,6(3 H ,7 H )-dione ( 4 ) displayed high affinity ( K i = 1 nM) and selectivity for the A 2B -AdoR versus A 1 , A 2A , and A 3 -AdoRs (A 1 /A 2B , A 2A /A 2B , and A 3 /A 2B selectivity ratios of 370, 1100, and 480, respectively). The synthesis and SAR of this novel class of compounds are presented herein.
Jeff Zablocki - One of the best experts on this subject based on the ideXlab platform.
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progress in the discovery of selective high affinity a2b Adenosine Receptor Antagonists as clinical candidates
Purinergic Signalling, 2009Co-Authors: Rao Kalla, Jeff ZablockiAbstract:The selective, high affinity A2B Adenosine Receptor (AdoR) Antagonists that were synthesized by several research groups should aid in determining the role of the A2B AdoR in inflammatory diseases like asthma or rheumatoid arthritis (RA) and angiogenic diseases like diabetic retinopathy or cancer. CV Therapeutics scientists discovered the selective, high affinity A2B AdoR antagonist 10, a 8-(4-pyrazolyl)-xanthine derivative [CVT-6883, Ki(hA2B) = 22 nM; Ki(hA1) = 1,940 nM; Ki(hA2A) = 3,280; and Ki(hA3) = 1,070 nM] that has favorable pharmacokinetic (PK) properties (t 1/2 = 4 h and F > 35% rat). Compound 10 demonstrated functional antagonism at the A2B AdoR (KB = 6 nM) and efficacy in a mouse model of asthma. In two phase 1 clinical trials, CVT-6883 was found to be safe, well tolerated, and suitable for once daily dosing. A second compound 20, 8-(5-pyrazolyl)-xanthine, has been nominated for development from Baraldi’s group in conjunction with King Pharmaceuticals that has favorable A2B AdoR affinity and selectivity [Ki(hA2B) = 5.5 nM; Ki(hA1) > 1,000 nM; Ki(hA2A) > 1,000; and Ki(hA3) > 1,000 nM], and it has been demonstrated to be a functional antagonist. A third compound 32, a 2-aminopyrimidine, from the Almirall group has high A2B AdoR affinity and selectivity [Ki(hA2B) = 17 nM; Ki(hA1) > 1,000 nM; Ki(hA2A) > 2,500; and Ki(hA3) > 1,000 nM], and 32 has been moved into preclinical safety testing. Since three highly selective, high affinity A2B AdoR Antagonists have been nominated for development with 10 (CVT-6883) being the furthest along in the development process, the role of the A2B AdoR in various disease states will soon be established.
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selective high affinity a2b Adenosine Receptor Antagonists n 1 monosubstituted 8 pyrazol 4 yl xanthines
Bioorganic & Medicinal Chemistry Letters, 2008Co-Authors: Rao Kalla, Elfatih Elzein, Thao Perry, Dewan Zeng, Art Gimbel, Ming Yang, Jeff ZablockiAbstract:A series of N-1 monosubstituted 8-pyrazolyl xanthines have been synthesized and evaluated for their affinity for the Adenosine Receptors (AdoRs). We have discovered two compounds 18 (CVT-7124) and 28 (CVT-6694) that display good affinity for the A2B AdoR (Ki = 6 nM and 7 nM, respectively) and greater selectivity for the human A1, A2A, and A3 AdoRs (>1000-, >830-, and >1500-fold; >850-, >700-, and >1280-fold, respectively). CVT-6694 has been shown to block the release of interleukin-6 and monocyte chemotactic protein-1 from bronchial smooth muscle cells (BSMC), a process believed to be promoted by activation of A2B AdoR.
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novel 1 3 disubstituted 8 1 benzyl 1h pyrazol 4 yl xanthines high affinity and selective a2b Adenosine Receptor Antagonists
Journal of Medicinal Chemistry, 2006Co-Authors: Rao Kalla, Elfatih Elzein, Thao Perry, Venkata P Palle, Vaibhav Varkhedkar, Arthur Gimbel, Tennig Maa, Dewan Zeng, Jeff ZablockiAbstract:Adenosine has been suggested to induce bronchial hyperresponsiveness in asthmatics, which is believed to be an A(2B) Adenosine Receptor (AdoR) mediated pathway. We hypothesize that a selective, high-affinity A(2B) AdoR antagonist may provide therapeutic benefit in the treatment of asthma. In an attempt to identify a high-affinity, selective antagonist for the A(2B) AdoR, we synthesized 8-(C-4-pyrazolyl) xanthines. Compound 22, 8-(1H-pyrazol-4-yl)-1,3-dipropyl xanthine, is a N-1 unsubstituted pyrazole derivative that has favorable binding affinity (K(i) = 9 nM) for the A(2B) AdoR, but it is only 2-fold selective versus the A(1) AdoR. Introduction of a benzyl group at the N-1-pyrazole position of 22 resulted in 19, which had moderate selectivity. The initial focus of the SAR study was on the preparation of substituted benzyl derivatives of 19 because the corresponding phenyl, phenethyl, and phenpropyl derivatives showed a decrease in A(2B) AdoR affinity and selectivity relative to 19. The preferred substitution on the phenyl ring of 19 contains an electron-withdrawing group, specifically F or CF(3) at the m-position, as in 33 and 36 respectively, increases the selectivity while retaining the affinity for the A(2B) AdoR. Exploring disubstitutions on the phenyl ring of derivatives 33 and36 led to the 2-chloro-5-trifluoromethylphenyl derivative 50, which retained the A(2B) AdoR affinity but enhanced the selectivity relative to 36. After optimization of the substitution on the 8-pyrazole xanthine, 1,3-disubstitution of the xanthine core was explored with methyl, ethyl, butyl, and isobutyl groups. In comparison to the corresponding dipropyl analogues, the smaller 1,3-dialkyl groups (methyl and ethyl) increased the A(2B) AdoR binding selectivity of the xanthine derivatives while retaining the affinity. However, the larger 1,3-dialkyl groups (isobutyl and butyl) resulted in a decrease in both A(2B) AdoR affinity and selectivity. This final SAR optimization led to the discovery of 1,3-dimethyl derivative 60, 8-(1-(3-(trifluoromethyl) benzyl)-1H-pyrazol-4-yl)-1,3-dimethyl xanthine, a high-affinity (K(i) = 1 nM) A(2B) AdoR antagonist with high selectivity (990-, 690-, and 1,000-) for the human A(1), A(2A,) and A(3) AdoRs.
Giampiero Spalluto - One of the best experts on this subject based on the ideXlab platform.
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Novel fluorescent hA3 Adenosine Receptor Antagonists.
Comitato organizzatore NPCF7, 2013Co-Authors: Federico Stephanie, Moro Stefano, Kozma Eszter, Kumar T. Santhosh, Jacobson, Kenneth A., Giampiero SpallutoAbstract:Activation of the Gi protein-coupled A3 Adenosine Receptor (AR) is associated with anticancer, antiischemic and anti-inflammatory effects. hA3 AR Antagonists are being examined as promising agents for the treatment of glaucoma.1 Fluorescent probes are useful tools to investigate specific subcellular components in cells, tissues and organisms. In high throughput screening, fluorescent ligands represents a safer, more powerful and more versatile alternative to radioligands.2 We have recently reported a series of pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine (PTP) based \ufb02uorophore-conjugated hA3 AR Antagonists.3 Unfortunately, none of them reached affinities in the nM range. Here we report a novel series of PTP based \ufb02uorophore-conjugated hA3 AR antagonist with an additional pharmacophoric group at the 5-position, in order to obtain more potent hA3 AR Antagonists. References 1. M\ufcller, C.E.; Jacobson, K.A. Recent developments in Adenosine Receptor ligands and their potential as novel drugs. Biochim. Biophys. Acta 2011, 1808, 1290-1308. 2. Kuder,K.; Kiec-Kononowicz, K. Fluorescent GPCR ligands as new tools in pharmacology. Curr. Med. Chem. 2008, 15, 2132\u20132143. 3. Kozma, E.; Kumar, T.S.; Federico, S.; Phan, K.; Balasubramanian, R.; Gao, Z.G.; Paoletta, S.; Moro, S.; Spalluto, G.; Jacobson, K.A. Novel fluorescent antagonist as a molecular probe in A3 Adenosine Receptor binding assays using flow cytometry. Biochem. Pharmacol. 2012, 83, 1552-1561
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Structural Investigations on a Novel Class of [1,2,4]Triazolo[1,5-c]pyrimidines as Adenosine Receptor Antagonists.
Società chimica Italiana, 2012Co-Authors: Federico Stephanie, Klotz Karl-norbert, Moro Stefano, Cacciari Barbara, Paoletta Silvia, Giampiero SpallutoAbstract:Adenosine Receptors (ARs) are members of the superfamily of G protein-coupled Receptors (GPCRs). There are four subtypes currently recognized: the A1AR, A2AAR, A2BAR and A3AR. The classical AR antagonist caffeine is the most consumed drug in the world. Its effects on the nervous system, such as enhancement of awareness and learning, have encouraged the investigation of selective AR Antagonists for the treatment of various nervous system conditions. (1) Several classes of heterocyclic derivatives have been reported as AR Antagonists with high levels of both affinity and selectivity. (2) The [1,2,4]-triazolo[1,5-c]pyrimidine nucleus possesses a low molecular weight and four nitrogen atoms, thus it may be a scaffold with promising pharmacokinetics properties. We have investigated substitutions at the 2, 5 and 8 positions, with the aim of obtaining potent Antagonists selective only for one of the four Adenosine Receptor subtypes. A Receptor-driven molecular modeling investigation has been carried out in order to support the experimental binding data and to justify the selectivity against the other Receptor subtypes. (1) Moro, S.; Gao, Z.G.; Jacobson, K.A.; Spalluto, G. Med. Res. Rev. 2006, 26, 131-159. (2) Muller, C.E.; Jacobson, K.A. Biochim. Biophys. Acta. 2011, 1808, 1290\u2013130
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[1,2,4]Triazolo[1,5-c]pyrimidine Nucleus as Adenosine Receptor Antagonists: Shift in Selectivity from A2A to A3 Adenosine Receptors.
Purine club, 2012Co-Authors: Federico Stephanie, Klotz Karl-norbert, Moro Stefano, Ciancetta Antonella, Cacciari Barbara, Paoletta Silvia, Giampiero SpallutoAbstract:[1,2,4]Triazolo[1,5-c]pyrimidine derivatives are reported in literature as A2A Adenosine Receptor (AR) Antagonists useful for the treatment of Parkinson\u2019s disease (PD), senile dementia and depression (1).[1] Several classes of heterocyclic derivatives have been reported as AR Antagonists.[2] Among them, the Schering compound, preladenant (2), a pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine (PTP) A2A antagonist (which is under phase III clinical trials for the treatment of PD), possesses the same lateral subtituent of compound 1.[2,3] In the [1,2,4]triazolo[1,5-c]pyrimidine compound (1) the pyrazole moiety of preladenant was substituted by a phenyl spacer, leading to a compound which displays the same affinity at the A2A AR. The [1,2,4]-triazolo[1,5-c]pyrimidine nucleus possesses a simpler structure and less nitrogen atoms than PTPs, thus it may be a scaffold with promising pharmacokinetics properties. So, starting from the similar behavior of [1,2,4]triazolo[1,5-c]pyrimidines and PTPs on ARs, and our experience on PTP as A3 AR Antagonists, we decided to explore the [1,2,4]triazolo[1,5-c]pyrimidine scaffold as Antagonists towards A3 AR. Initially, we introduced on the bicyclic scaffold the same substituents those give affinity and selectivity at the A3 AR in the PTP nucleus. On the basis of obtained results, the optimization of substitutions allow us, after 4 series (147compounds) of [1,2,4]triazolo[1,5-c]pyrimidine derivatives, to discover a potent and selective A3 AR antagonist, with a Ki of 0.47 nM. [1] Kyowa Hakko Kogyo Cp., Ltd., Tokyo (JP). Shimada, J.; Imma, H.; Osakada, N.; Shiozaki, S.; Kanda, T.; Kuwana, Y. [1,2,4]Triazolo[1,5-c]pyrimidine derivatives. 2003, US6545000. [2] Muller, C.E.; Jacobson, K.A. Recent developments in Adenosine Receptor ligands and their potential as novel drugs. Biochim. Biophys. Acta. 2011, 1808, 1290\u20131308. [3] Neustadt, B.R.; Hao, J., Lindo, N.; Greenlee, W.J.; Stamford, A.W.; Tulshian, D.; Ongini, E.; Hunter, J.; Monopoli, A.; Bertorelli, R.; Foster, C.; Arik, L.; Lachowicz, J.; Nga, K.; Feng, K.I. Potent, selective, and orally active Adenosine A2A Receptor Antagonists: arylpiperazine derivatives of pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines. Bioorg. Med. Chem. Lett. 2007, 17, 1376\u20131380
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New 2,6,9-trisubstituted adenines as Adenosine Receptor Antagonists: a preliminary SAR profile
Purinergic Signalling, 2007Co-Authors: Catia Lambertucci, Gloria Cristalli, Dhuldeo D. Kachare, Chiara Bolcato, Karl-norbert Klotz, Giampiero Spalluto, Rosaria VolpiniAbstract:A new series of 2,6,9-trisubstituted adenines ( 5–14 ) have been prepared and evaluated in radioligand binding studies for their affinity at the human A_1, A_2A and A_3 Adenosine Receptors and in adenylyl cyclase experiments for their potency at the human A_2B subtype. From this preliminary study the conclusion can be drawn that introduction of bulky chains at the N ^6 position of 9-propyladenine significantly increased binding affinity at the human A_1 and A_3 Adenosine Receptors, while the presence of a chlorine atom at the 2 position resulted in a not univocal effect, depending on the Receptor subtype and/or on the substituent present in the N ^6 position. However, in all cases, the presence in the 2 position of a chlorine atom favoured the interaction with the A_2A subtype. These results demonstrated that, although the synthesized compounds were found to be quite inactive at the human A_2B subtype, adenine is a useful template for further development of simplified Adenosine Receptor Antagonists with distinct Receptor selectivity profiles.
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autocorrelation of molecular electrostatic potential surface properties combined with partial least squares analysis as alternative attractive tool to generate ligand based 3d qsars
Current Drug Discovery Technologies, 2005Co-Authors: Stefano Moro, Magdalena Bacilieri, Cristina Ferrari, Giampiero SpallutoAbstract:A database of 106 human A3 Adenosine Receptor Antagonists was used to derive two alternative PLS models: one starting from CoMFA descriptors and the other starting from the autocorrelation descriptors. The peculiarity of this work is the introduction of autocorrelation vectors as molecular descriptors for the PLS analysis. The autocorrelation allows comparing molecules (and their properties) with different structures and with different spatial orientation without any previous alignment. In particular, Molecular Electrostatic Potential (MEP) was the property computed and its information encoded in autocorrelation vectors. The 3D spatial distribution and the values of the electrostatic potential is in fact largely responsible for the binding of a substrate to its Receptor binding site. Validation was done with an external test set and the results of the two models were compared. Interestingly, our preliminary results seem to indicate that this new alternative approach could robustly compete with the already well consolidated CoMFA approach. In particular, we have suggested that it could be a very interesting tool to filter large structural database in several virtual screening applications.