Xanthines with C8 chiral substituents as potent and selective adenosine A1 antagonists

Peet, Norton P.; Lentz, Nelsen L.; Dudley, Mark W.; Ogden, Ann Marie L.; McCarty, Deborah R.; Racke, Margaret M.

doi:10.1021/jm00077a004

Cited by 11 publications

(8 citation statements)

References 7 publications

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“…Besides 8-phenylxanthine derivatives 8-benzyl- ( 62 ) and 8-phenylethyl-substituted xanthines ( 59–61 ) have also been investigated and optimized with respect to A 1 affinity (Peet et al 1993). Among 8-(arylalkyl)-xanthine derivatives, 3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-{2-ethyl(2-hydroxyethyl)amino]ethyl}-1-propyl-3,7-dihydropurine-2,6-dione (L-97-1, 62 ) is weaker in binding than typical 8-arylxanthine probes, but is a water soluble A 1 AR antagonist bearing a basic substituent at N7 that has been proposed for the treatment of asthma (Obiefuna et al, 2005).…”

Section: Adenosine A1 Receptor Antagonistsmentioning

confidence: 99%

“…Among 8-(arylalkyl)-xanthine derivatives, 3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-{2-ethyl(2-hydroxyethyl)amino]ethyl}-1-propyl-3,7-dihydropurine-2,6-dione (L-97-1, 62 ) is weaker in binding than typical 8-arylxanthine probes, but is a water soluble A 1 AR antagonist bearing a basic substituent at N7 that has been proposed for the treatment of asthma (Obiefuna et al, 2005). 1,3-Dipropyl-8-phenylethyl-xanthine derivatives with a methyl ( 59–60 ) or ethyl ( 61 ) substituent at the α-carbon atom adjacent to the xanthine C8-position showed particularly high affinity and selectivity for A 1 AR with a configurational preference for the ( R )- over the ( S )-enantiomer (Peet et al 1993). …”

Section: Adenosine A1 Receptor Antagonistsmentioning

confidence: 99%

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Xanthines as Adenosine Receptor Antagonists

Müller

Jacobson

2010

Handbook of Experimental Pharmacology

115

109

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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 analogs have subsequently been 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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Section: Adenosine A1 Receptor Antagonistsmentioning

confidence: 99%

Section: Adenosine A1 Receptor Antagonistsmentioning

confidence: 99%

Xanthines as Adenosine Receptor Antagonists

Müller

Jacobson

2010

Handbook of Experimental Pharmacology

115

109

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“…The chemoselective hydrolysis of the exocyclic amide group of ()-19 was accomplished using LiOOH, generated in situ from H 2 O 2 and LiOH, to give carboxylic acid (À)-20 and to regain oxazolidinone ()-15 (Scheme 4) [22] (for an earlier synthesis of racemic (AE)-20, see [23]). Since the amide coupling with pyridine-3,4-diamine described in Sect.…”

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confidence: 99%

Second‐Generation Inhibitors for the Metalloprotease Neprilysin Based on Bicyclic Heteroaromatic Scaffolds: Synthesis, Biological Activity, and X‐Ray Crystal‐Structure Analysis

Sahli

Frank

Schweizer

et al. 2005

Helvetica Chimica Acta

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A new class of nonpeptidic inhibitors of the Zn II -dependent metalloprotease neprilysin with IC 50 values in the nanomolar activity range (0.034 ± 0.30 mm) were developed based on structure-based de novo design (Figs. 1 and 2). The inhibitors feature benzimidazole and imidazo [4,5-c]pyridine moieties as central scaffolds to undergo H-bonding to Asn542 and Arg717 and to engage in favorable p-p stacking interactions with the imidazole ring of His711. The platform is decorated with a thiol vector to coordinate to the Zn II ion and an aryl residue to occupy the hydrophobic S1' pocket, but lack a substituent for binding in the S2' pocket, which remains closed by the side chains of Phe106 and Arg110 when not occupied. The enantioselective syntheses of the active compounds ()-1, ()-2, ()-25, and ()-26 were accomplished using Evans auxiliaries (Schemes 2, 4, and 5). The inhibitors ()-2 and ()-26 with an imidazo[4,5-c]pyridine core are ca. 8 times more active than those with a benzimidazole core (()-1 and ()-25) ( Table 1). The predicted binding mode was established by X-ray analysis of the complex of neprilysin with ()-2 at 2.25-resolution (Fig. 4 and Table 2). The ligand coordinates with its sulfanyl residue to the Zn II ion, and the benzyl residue occupies the S1' pocket. The 1H-imidazole moiety of the central scaffold forms the required H-bonds to the side chains of Asn542 and Arg717. The heterobicyclic platform additionally undergoes p-p stacking with the side chain of His711 as well as edge-to-face-type interactions with the side chain of Trp693. According to the X-ray analysis, the substantial advantage in biological activity of the imidazopyridine inhibitors over the benzimidazole ligands arises from favorable interactions of the pyridine N-atom in the former with the side chain of Arg102. Unexpectedly, replacement of the phenyl group pointing into the deep S1' pocket by a biphenyl group does not enhance the binding affinity for this class of inhibitors.1. Introduction. ± In the preceding paper [1], we described a new class of inhibitors of the metalloprotease neprilysin with a central 1H-imidazole platform, featuring IC 50 values (IC 50 : concentration of inhibitor at which 50% V max is observed) in the low micromolar range. The de novo design of these compounds was based on the X-ray crystal structure of NEP complexed with phosphoramidon (Protein Data Bank (PDB) file name 1DMT) [2]. For the design of the second-generation inhibitors, we reverted to an unpublished X-ray crystal structure [3] of NEP complexed with the inhibitor thiorphan [4]. During the analysis, we carefully compared the active sites of the two

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“…aTetralol (1) is a chiral secondary alcohol used as a substrate 15) or starting material in enantioselective syntheses. 16,17) 2-Phenylpropionic acid (2) is an acidic compound that possesses a carboxyl group and is used to synthesize optically active compounds, for example, xanthine derivatives 18) and tetrapeptides. 19) 1-Phenylethylamine (3) is used in enantioselective syntheses of a-substituted primary amines 20) and as a chiral reagent in the preparation of enantiopure compounds.…”

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confidence: 99%

Sub- and Supercritical Chiral Separation of Racemic Compounds on Columns with Stationary Phases Having Different Functional Groups

Kasai

Tsubuki

Matsuo

et al. 2005

CHEMICAL & PHARMACEUTICAL BULLETIN

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Separation of the enantiomers of each of three different racemates, neutral rac-a a-tetralol, acidic rac-2-phenylpropionic acid, and basic rac-1-phenylethylamine, using subcritical and supercritical fluid chromatography with two different chiral stationary phases, heptakis(2,3,6-tri-O-methyl)-b b-cyclodextrin (Sumichiral OA-7500 column) and tris(3,5-dimethylphenylcarbamate) of amylose (Chiralpak AD-H column), was compared. The elution order of the enantiomers of the three racemates was determined, and the effects of the type of alcohol modifier, column oven temperature, mobile phase composition, flow rate, and pressure were examined. The most appropriate column oven temperature depended on both the type of alcohol modifier and the compound analyzed. Lower alcohol content improved the peak separation of both rac-a a-tetralol on the Sumichiral OA-7500 column and rac-1-phenylethylamine on the Chiralpak AD-H column, while the same phenomenon was not observed with either rac-a a-tetralol or rac-2-phenylpropionic acid on the Chiralpak AD-H column. Decreasing outlet pressure improved the peak separation obtained with rac-2-phenylpropionic acid, but had little effect on either rac-a atetralol or rac-1-phenylethylamine.

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Xanthines with C8 chiral substituents as potent and selective adenosine A1 antagonists

Cited by 11 publications

References 7 publications

Xanthines as Adenosine Receptor Antagonists

Xanthines as Adenosine Receptor Antagonists

Second‐Generation Inhibitors for the Metalloprotease Neprilysin Based on Bicyclic Heteroaromatic Scaffolds: Synthesis, Biological Activity, and X‐Ray Crystal‐Structure Analysis

Sub- and Supercritical Chiral Separation of Racemic Compounds on Columns with Stationary Phases Having Different Functional Groups

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