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Anilide Derivatives of an 8-Phenylxanthine Carboxylic Congener Are Highly Potent and Selective Antagonists at Human A2B Adenosine Receptors

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Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0810, and Department of Internal Medicine and Molecular Physiology & Biological Physics, University of Virginia, Box MR4 6012, Health Science Center, Charlottesville, Virginia 22908
Cite this: J. Med. Chem. 2000, 43, 6, 1165–1172
Publication Date (Web):February 26, 2000
https://doi.org/10.1021/jm990421v
Copyright © 2000 American Chemical Society

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    Abstract

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    No highly selective antagonists of the A2B adenosine receptor (AR) have been reported; however such antagonists have therapeutic potential as antiasthmatic agents. Here we report the synthesis of potent and selective A2B receptor antagonists. The structure−activity relationships (SAR) of 8-phenyl-1,3-di-(n-propyl)xanthine derivatives in binding to recombinant human A2B ARs in HEK-293 cells (HEK-A2B) and at other AR subtypes were explored. Various amide derivatives of 8-[4-[[carboxymethyl]oxy]phenyl]-1,3-di-(n-propyl)xanthine, 4a, were synthesized. A comparison of aryl, alkyl, and aralkyl amides demonstrated that simple anilides, particularly those substituted in the para-position with electron-withdrawing groups, such as nitro, cyano, and acetyl, bind selectively to human A2B receptors in the range of 1−3 nM. The unsubstituted anilide 12 had a Ki value at A2B receptors of 1.48 nM but was only moderately selective versus human A1/A2A receptors and nonselective versus rat A1 receptors. Highly potent and selective A2B antagonists were a p-aminoacetophenone derivative 20 (Ki value 1.39 nM) and a p-cyanoanilide 27 (Ki value 1.97 nM). Compound 27 was 400-, 245-, and 123-fold selective for human A2B receptors versus human A1/A2A/A3 receptors, respectively, and 8.5- and 310-fold selective versus rat A1/A2A receptors, respectively. Substitution of the 1,3-dipropyl groups with 1,3-diethyl offered no disadvantage for selectivity, and high affinities at A2B receptors were maintained. Substitution of the p-carboxymethyloxy group of 4a and its amides with acrylic acid decreased affinity at A2B receptors while increasing affinity at A1 receptors. 1,3-Di(cyclohexylmethyl) groups greatly reduced affinity at ARs, although the p-carboxymethyloxy derivative 9 was moderately selective for A2B receptors. Several selective A2B antagonists inhibited NECA-stimulated calcium mobilization in HEK-A2B cells.

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     National Institute of Diabetes, Digestive and Kidney Diseases.

     University of Virginia.

    *

     Correspondence to:  Dr. K. A. Jacobson, Bldg. 8A, Rm. B1A-19, NIH, NIDDK, LBC, Bethesda, MD 20892-0810. Tel:  (301) 496-9024. Fax:  (301) 480-8422. E-mail:  [email protected].

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    Characterization of xanthine derivates by proton NMR and elemental analyses. This material is available free of charge via the Internet at http://pubs.acs.org.

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