Structure determination of metabolites isolated from urine and bile after administration of AY4166, a novel D-phenylalanine-derivative hypoglycemic agent

被引:31
作者
Takesada, H [1 ]
Matsuda, K [1 ]
Ohtake, R [1 ]
Mihara, R [1 ]
Ono, I [1 ]
Tanaka, K [1 ]
Naito, M [1 ]
Yatagai, M [1 ]
Suzuki, E [1 ]
机构
[1] AJINOMOTO CO INC,CENT RES LABS,KAWASAKI KU,KAWASAKI,KANAGAWA 210,JAPAN
关键词
D O I
10.1016/0968-0896(96)00187-3
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Molecular structures of 10 metabolites, which were isolated from urine (M1-M8) or bile (M9 and MIG) after administration of AY4166 (N-(trans-4-isopropylcyclohexanecarbonyl)-D-phenylalanine), a novel amino acid derivative with hypoglycemic activity, have been elucidated by mass spectrometry and nuclear magnetic resonance. Four of these (M1, M2, M3 and M8) were determined to be hydroxyl derivatives of AY4166, two (M9 and M10) were carboxylate derivatives via oxidization of M2 and M3, three (M4, M5 and M6) were glucronic acid conjugates and the other (M7) was a dehydro derivative. The estimated structures for M1, M2, M3, M7, Ms, M9 and MIO were confirmed by the coincidence of the retention time of HPLC, MS and H-1 NMR spectra between the isolated metabolites and authentic synthesized substances. For three glucronic acid conjugates, M4, M5 and M6, structural confirmation was performed by a selective enzymatic digestion with beta-glucronidase. M1 and M2/3 were about 5-6 and 3 times less potent than AY4166, respectively, and M7 was almost as potent as AY4166. Copyright (C) 1996 Elsevier Science Ltd
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页码:1771 / 1781
页数:11
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