Metabolic activation of fluoropyrrolidine dipeptidyl peptidase-IV inhibitors by rat liver microsomes

被引:33
作者
Xu, SY
Zhu, B
Teffera, Y
Pan, DE
Caldwell, CG
Doss, G
Stearns, RA
Evans, DC
Beconi, MG
机构
[1] Merck Res Labs, Dept Drug Metab, Rahway, NJ 07065 USA
[2] Merck Res Labs, Dept Med Chem, Rahway, NJ 07065 USA
关键词
D O I
10.1124/dmd.104.001842
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The current study evaluated the potential for two dipeptidyl peptidase-IV (DPP-IV) inhibitor analogs (1S)-1-(trans-4-{[(4-trifluoromethoxyphenyl)sulfonyl]amino}cyclohexyl)-2-[(3S)-3-fluoropyrrolidin-1-yl]-2-oxoethanaminium chloride and (1S)-1(trans-4-{[(2,4-difluorophenyl)sulfonyl]amino}cyclohexyl)-2-[(3S)-3-fluoropyrrolidin-1-yl]-2- oxoethanaminium chloride (MRL-A and MRL-B), containing a fluoropyrrolidine moiety in the structure, to undergo metabolic activation. The irreversible binding of these tritium-labeled compounds to rat liver microsomal protein was time- and NADPH-dependent and was attenuated by the addition of reduced glutathione (GSH) or N-acetylcysteine (NAC) to the incubation, indicating that chemically reactive intermediates were formed and trapped by these nucleophiles. Mass spectrometric analyses and further trapping experiments with semicarbazide indicated that the fluoropyrrolidine ring had undergone sequential oxidation and defluorination events resulting in the formation of GSH or NAC conjugates of the pyrrolidine moiety. The bioactivation of MRL-A was catalyzed primarily by rat recombinant CYP3A1 and CYP3A2. Pretreatment of rats with prototypic CYP3A1 and 3A2 inducers (pregnenolone-16alpha-carbonitrile and dexamethasone) enhanced the extent of bioactivation which, in turn, led to a higher degree of in vitro irreversible binding to microsomal proteins (5- and 9-fold increase, respectively). Herein, we describe studies that demonstrate that the fluoropyrrolidine ring is prone to metabolic activation and that GSH or NAC can trap the reactive intermediates to form adducts that provide insight into the mechanisms of bioactivation.
引用
收藏
页码:121 / 130
页数:10
相关论文
共 22 条
[1]   Inhibition of dipeptidyl peptidase IV improves metabolic control over a 4-week study period in type 2 diabetes [J].
Ahrén, B ;
Simonsson, E ;
Larsson, H ;
Landin-Olsson, M ;
Torgeirsson, H ;
Jansson, PA ;
Sandqvist, M ;
Båvenholm, P ;
Efendic, S ;
Eriksson, JW ;
Dickinson, S ;
Holmes, D .
DIABETES CARE, 2002, 25 (05) :869-875
[2]   Pyrrolidides: Synthesis and structure-activity relationship as inhibitors of dipeptidyl peptidase IV [J].
Augustyns, KJL ;
Lambeir, AM ;
Borloo, M ;
DeMeester, I ;
Vedernikova, I ;
Vanhoof, G ;
Hendriks, D ;
Scharpe, S ;
Haemers, A .
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 1997, 32 (04) :301-309
[3]  
Baillie TA, 2001, ADV EXP MED BIOL, V500, P45
[4]   MASS-SPECTROMETRY IN THE ANALYSIS OF GLUTATHIONE CONJUGATES [J].
BAILLIE, TA ;
DAVIS, MR .
BIOLOGICAL MASS SPECTROMETRY, 1993, 22 (06) :319-325
[5]   Fluoropyrrolidine amides as dipeptidyl peptidase IV inhibitors [J].
Caldwell, CG ;
Chen, P ;
He, JF ;
Parmee, ER ;
Leiting, B ;
Marsilio, F ;
Patel, RA ;
Wu, JK ;
Eiermann, GJ ;
Petrov, A ;
He, HB ;
Lyons, KA ;
Thornberry, NA ;
Weber, AE .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (05) :1265-1268
[6]   Therapeutic potential of dipeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes [J].
Drucker, DJ .
EXPERT OPINION ON INVESTIGATIONAL DRUGS, 2003, 12 (01) :87-100
[7]   Drug-protein adducts: An industry perspective on minimizing the potential for drug bioactivation in drug discovery and development [J].
Evans, DC ;
Watt, AP ;
Nicoll-Griffith, DA ;
Baillie, TA .
CHEMICAL RESEARCH IN TOXICOLOGY, 2004, 17 (01) :3-16
[8]  
FOURNEL S, 1983, INT J CLIN PHARM RES, V3, P431
[9]   Dipeptidyl peptidase IV-resistant [D-Ala2]glucose-dependent insulinotropic polypeptide (GIP) improves glucose tolerance in normal and obese diabetic rats [J].
Hinke, SA ;
Gelling, RW ;
Pederson, RA ;
Manhart, S ;
Nian, C ;
Demuth, HU ;
McIntosh, CHS .
DIABETES, 2002, 51 (03) :652-661
[10]  
Hoffmann T, 2001, INT CONGR SER, V1218, P381