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.
The anticonvulsant carbamazepine 1 is associated with adverse drug reactions (ADRs), including hepatotoxicity; oxidative metabolism of 1 has been implicated in the pathogenesis of the ADRs. We report the synthesis and evaluation of 2-monohalo and 2,8-dihalo analogues of 1 that were intended to minimize reactive metabolite formation via arene oxidation and 10,11-epoxidation. Halo analogues were obtained either by rearrangement of halogenated N-arylindoles or from specifically halogenated iminodibenzyl derivatives. In rat hepatocytes, none of the analogues underwent oxidative dehalogenation or glutathione adduction. Some formation of the 10,11-epoxide still occurred, but aromatic hydroxylation was not seen with the exception of 2-fluoro, which allowed minor monohydroxylation. Complete inhibition of aromatic hydroxylation required at least monochlorination or difluorination of 1. In human liver microsomes, difluoro analogue 5b underwent 10,11-epoxidation but gave no arene oxidation.
Carbohydrates U 0500Efficient Synthesis of 1β-O-Acyl Glucuronides via Selective Acylation of Allyl or Benzyl D-Glucuronate. -An efficient two-step synthesis of O-acyl glucuronides like (IV) is presented, involving the regio-and stereoselective acylation of benzyl (I) or allyl (V) glucuronate esters with various acids at the 1-position followed by deprotection of the glucuronic acid (transfer hydrogenation or hydrolysis, respectively). A wide range of acyl groups is successfully introduced, including those derived from biologically active acids like diclofenac (IIf), zomepirac (IIe) or ibuprofen (VI). -(BOWKETT, E. R.; HARDING, J. R.; MAGGS, J. L.; PARK, B. K.; PERRIE, J. A.; STACHULSKI*, A. V.; Tetrahedron 63 (2007) 32, 7596-7605; Robert Robinson Lab., Dep. Chem., Univ. Liverpool, Liverpool L69 7ZD, UK; Eng.) -Mischke 46-174
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