- Preparation, Properties, Reactions, and Adenosine Receptor Affinities of Sulfophenylxanthine Nitrophenyl Esters: Toward the Development of Sulfonic Acid Prodrugs with Peroral Bioavailability
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Many currently known antagonists for P2 purinergic receptors are anionic molecules bearing one or several phenylsulfonate groups. Among the P1 (adenosine) receptor antagonists, the xanthine phenylsulfonates are a potent class of compounds. Due to their high acidity, phenylsulfonates are negatively charged at physiologic pH values and do not easily penetrate cell membranes. The present study was aimed at developing lipophilic, perorally bioavailable prodrugs of sulfonates by converting them into chemically stable nitrophenyl esters. Initial stability tests at different pH values using nitrophenyl tosylates as model compounds showed that m-nitrophenyl esters were stable over a wide pH range, while the ortho and para isomers were less stable under strongly acidic or basic conditions. A series of m- and p-nitrophenyl esters of p-sulfophenylxanthine derivatives were synthesized as model compounds. The target xanthine derivatives were obtained in high yields by condensation of the appropriate 5,6-diaminouracils with 4-(nitrophenoxysulfonyl)benzoic acids in the presence of a carbodiimide, followed by ring closure with polyphosphoric acid trimethylsilyl ester. The chemical and enzymatic stability of the m-nitrophenyl esters was investigated in vitro by means of capillary electrophoresis. High stability in aqueous solution, in artificial gastric acid, and in serum was observed. However, compound 5d, used as a prototypic xanthine m-nitrophenylsulfonate, was hydrolyzed by rat liver homogenate indicating an enzymatic pathway of hydrolysis. Thus, nitrophenyl esters of sulfonic acids have a potential as peroral prodrugs of drugs bearing a sulfonate group. The nitrophenyl esters of sulfophenylxanthines were additionally investigated for their adenosine receptor affinities. They showed high affinity at A 2, A2A, and A2B, but not at A3 ARs. One of the most potent compounds was 1-propyl-8-[4-[[p-nitrophenoxy]sulfonyl]-phenyl]xanthine (9d), a mixed A 1/A2B antagonist (KiA1 3.6 nM, KiA2B 5.4 nM) selective versus the other subtypes. As a further result of this study, the m-nitrophenoxy group was found to be a suitable protecting group for sulfonates in organic synthesis due to its high lipophilicity and stability; it can be split off under strongly basic conditions. This new protection strategy allowed for the upscaling of the synthesis of 1-propyl-8-p-sulfophenylxanthine (PSB-1115), a selective A 2B antagonist.
- Yan, Luo,Müller, Christa E.
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p. 1031 - 1043
(2007/10/03)
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- 1,8-Disubstituted xanthine derivatives: Synthesis of potent A2B-selective adenosine receptor antagonists
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3-Unsubstituted xanthine derivatives bearing a cyclopentyl or a phenyl residue in the 8-position were synthesized and developed as A2B adenosine receptor antagonists. Compounds bearing polar substituents were prepared to obtain water-soluble derivatives. 1-Alkyl-8-phenylxanthine derivatives were found to exhibit high affinity for A2B adenosine receptors (ARs). 1,8-Disubstituted xanthine derivatives were equipotent to or more potent than 1,3,8-trisubstituted xanthines at A2B ARs, but generally less potent at A1 and A2A, and much less potent at A3 ARs. Thus, the new compounds exhibited increased A2B selectivity versus all other AR subtypes. 9-Deazaxanthines (pyrrolo[2,3-d]pyrimidindiones) appeared to be less potent at A2B ARs than the corresponding xanthine derivatives. 1-Propyl-8-p-sulfophenylxanthine (17) was the most selective compound of the present series, exhibiting a Ki value of 53 nM at human A2B ARs and showing greater than 180-fold selectivity versus human A1 ARs. Compound 17 was also highly selective versus rat A1 ARs (41-fold) and versus the other human AR subtypes (A2A > 400-fold and A3 > 180-fold). The compound is highly water-soluble due to its sulfonate function. 1-Butyl-8-p-carboxyphenylxanthine (10), another polar analogue bearing a carboxylate function, exhibited a Ki value of 24 nM for A2B ARs, 49-fold selectivity versus human and 20-fold selectivity versus rat A1 ARs, and greater than 150-fold selectivity versus human A2A and A3 ARs. 8-[4-(2-Hydroxyethylamino)-2-oxoethoxy)phenyl]-1-propylxanthine (29) and 1-butyl-8-[4-(4-benzyl)piperazino-2-oxoethoxy)phenyl]xanthine (35) were among the most potent A2B antagonists showing Ki values at A2B ARs of 1 nM, 57-fold (29) and 94-fold (35) selectivity versus human A1, & ca. 30-fold selectivity versus rat A1, and greater than 400-fold selectivity versus human A2A and A3 ARs. The new potent, selective, water-soluble A2B antagonists may be useful research tools for investigating A2B receptor function.
- Hayallah, Alaa M.,Sandoval-Ramírez, Jesús,Reith, Ulrike,Schobert, Ulrike,Preiss, Birgit,Schumacher, Britta,Daly, John W.,Müller, Christa E.
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p. 1500 - 1510
(2007/10/03)
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- Synthesis of Paraxanthine Analogs (1,7-Disubstituted Xanthines) and Other Xanthines Unsubstituted at the 3-Position: Structure-Activity Relationships at Adenosine Receptors
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Synthetic procedures for the preparation of various 3-unsubstituted xanthines, including paraxanthine analogs (1,7-disubstituted xanthines) and 1,8-disubstituted xanthines, were developed.Sylylation of 1-substituted xanthines followed by alkylation at the 7-position provides a facile route to paraxanthine analogs.Regioselective alkylation of tris(trimethylsilyl)-6-aminouracil provides 3-substituted 6-aminouracils, which are converted to 1,8-disubstituted xanthines by standard procedures.The ring closure of 3-substituted 5-cyclopentanecarboxamido- and 5-(benzoylamino)-6-aminouracils requires drastic reaction conditions.Affinity for brain A1 and A2 adenosine receptors was determined in binding assays for these and other xanthines with substituents in 1-, 3-, 7-, 8-, and 9-positions.Substitution at the 1-position was necessary for high affinity at adenosine receptors. 1,3-Disubstituted xanthines generally had higher affinity than 1,7-disubstituted xanthines. 1,8-Disubstituted xanthines had high affinity for adenosine receptors; some were highly selective for A1 receptors.
- Mueller, Christa E.,Shi, Dan,Manning, Malcolm,Daly, John W.
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p. 3341 - 3349
(2007/10/02)
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