Kim, Yong-Chul published the artcileAnilide derivatives of an 8-phenylxanthine carboxylic congener are highly potent and selective antagonists at human A2B adenosine receptors, Category: amides-buliding-blocks, the publication is Journal of Medicinal Chemistry (2000), 43(6), 1165-1172, database is CAplus and MEDLINE.
No highly selective antagonists of the A2B adenosine receptor (AR) have been reported; however such antagonists have therapeutic potential as antiasthmatic agents. Here the synthesis of potent and selective A2B receptor Antagonists is reported. 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, I (R1 = n-Pr, X = OCH2, R2 = OH) (II), 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 I (R1 = n-Pr, X = OCH2, R2 = NHPh) had a Ki value at A2B receptors of 1.48 nM but was only moderately selective vs. human A1/A2A receptors and nonselective vs. rat A1 receptors. Highly potent and selective A2B antagonists were a p-aminoacetophenone derivative I (R1 = n-Pr, X = OCH2, R2 = 4-MeOC6H4NH) (Ki value 1.39 nM) and a p-cyanoanilide I (R1 = n-Pr, X = OCH2, R2 = NHC6H4CN-4) (III) (Ki value 1.97 nM). Compound III was 400-, 245-, and 123-fold selective for human A2B receptors vs. human A1/A2A/A3 receptors, resp., and 8.5- and 310-fold selective vs. rat A1/A2A receptors, resp. Substitution of the 1,3-di-Pr groups with 1,3-di-Et offered no disadvantage for selectivity, and high affinities at A2B receptors were maintained. Substitution of the p-carboxymethyloxy group of II 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 I (R1 = cyclohexylmethyl, X = CH:CH, R2 = OH) was moderately selective for A2B receptors. Several selective A2B antagonists inhibited NECA-stimulated calcium mobilization in HEK-A2B cells.
Journal of Medicinal Chemistry published new progress about 264622-53-9. 264622-53-9 belongs to amides-buliding-blocks, auxiliary class GPCR/G Protein,Adenosine Receptor, name is N-(4-Acetylphenyl)-2-(4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)phenoxy)acetamide, and the molecular formula is C27H29N5O5, Category: amides-buliding-blocks.
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https://en.wikipedia.org/wiki/Amide,
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