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Cyclization of the acyl glucuronide metabolite of a neutral endopeptidase inhibitor to an electrophilic glutarimide: synthesis, reactivity, and mechanistic analysis.

Abstract：

:The neutral endopeptidase inhibitor (2R)-2-[(1-{[(5-ethyl-1,3,4-thiadiazol-2-yl)amino]carbonyl}cyclopentyl)methyl]pentanoic acid 2 is metabolized to acyl glucuronide 3. Unprecedentedly, at pH 7.4, 3 does not undergo the O-acyl migration characteristic of acyl glucuronides but rapid, eliminative cyclization (t1/2 at 37 degrees C, 10.2 min) to glutarimide 4. Glucuronide 3 was synthesized efficiently via acylation of benzylglucuronate with N-benzyloxymethyl-protected 2. Glucuronide and imide reacted rapidly in aqueous solution, pH 7.4, with amino acids and glutathione to form stable amides and unstable thioesters. Imide 4 acylated eight lysine Nepsilon-amino groups of human serum albumin. Rapid cyclization of 3 was attributed to attack on the ester linkage by an unusually nucleophilic glutaramide NH (pKa in 2 = 9.76). N-propyl 3 was refractory to acyl migration and cyclization. This suggested a synthetic strategy for preparing analogues of 2 that form chemically stable acyl glucuronides.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Meng X,Maggs JL,Pryde DC,Planken S,Jenkins RE,Peakman TM,Beaumont K,Kohl C,Park BK,Stachulski AV

doi

10.1021/jm0706766

subject

Has Abstract

pub_date

2007-11-29 00:00:00

pages

6165-76

issue

24

eissn

0022-2623

issn

1520-4804

journal_volume

50

pub_type

杂志文章

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