Cyclization of the acyl glucuronide metabolite of a neutral endopeptidase inhibitor to an electrophilic glutarimide: synthesis, reactivity, and mechanistic analysis.
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.
Meng
Xiaoli
X
The Robert Robinson Laboratories, Department of Chemistry, University of Liverpool, Liverpool, United Kingdom.
Maggs
James L
JL
Pryde
David C
DC
Planken
Simon
S
Jenkins
Rosalind E
RE
Peakman
Torren M
TM
Beaumont
Kevin
K
Kohl
Christopher
C
Park
B Kevin
BK
Stachulski
Andrew V
AV
D000818:Animals; D003500:Cyclization; D020719:Glucuronides / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D010421:Pentanoic Acids / Q000737:chemistry* / Q000378:metabolism*; D010881:Piperidones / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D012709:Serum Albumin / Q000737:chemistry; D013237:Stereoisomerism; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism* / Q000493:pharmacokinetics
C513162:2-(1-((2-ethyl-1,3,4-thiadiazol-5-yl)aminocarbonyl)cyclopentyl)pentanoic acid; C526820:7-(5-ethyl-1,3,4-thiadiazol-2-yl)-9-propyl-7-azaspiro(4,5)decane-6,8-dione; D020719:Glucuronides; D010421:Pentanoic Acids; D010881:Piperidones; D012709:Serum Albumin; D013830:Thiadiazoles; D015260:Neprilysin