Cyclization of the Acyl Glucuronide Metabolite of a Neutral Endopeptidase Inhibitor to an Electrophilic Glutarimide:  Synthesis, Reactivity, and Mechanistic Analysis

• Published in: Journal of medicinal chemistry 2007-11, Vol.50 (24), p.6165-6176
• Main Authors: Meng, Xiaoli, Maggs, James L, Pryde, David C, Planken, Simon, Jenkins, Rosalind E, Peakman, Torren M, Beaumont, Kevin, Kohl, Christopher, Park, B. Kevin, Stachulski, Andrew V
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cyclization; Glucuronides - chemistry; Humans; Hydrogen-Ion Concentration; Hydrolysis; Male; Medical sciences; Miscellaneous; Neprilysin - antagonists & inhibitors; Neprilysin - chemistry; Pentanoic Acids - chemistry; Pentanoic Acids - metabolism; Pharmacology. Drug treatments; Piperidones - chemical synthesis; Piperidones - chemistry; Piperidones - pharmacokinetics; Rats; Rats, Wistar; Serum Albumin - chemistry; Stereoisomerism; Thiadiazoles - chemical synthesis; Thiadiazoles - chemistry; Thiadiazoles - metabolism; Thiadiazoles - pharmacokinetics
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0706766

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 (t 1/2 at 37 °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 Nε-amino groups of human serum albumin. Rapid cyclization of 3 was attributed to attack on the ester linkage by an unusually nucleophilic glutaramide NH (pK a 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.