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Stereochemistry of the Carbonyl Reduction of MSDC‐0602, An mTOT‐modulating Insulin‐sensitizer for the Treatment of Nonalcoholic Steatohepatitis (NASH)
Author(s) -
Adams Wade J,
Yousey Thad,
Bourdon Kelly,
Talay Susan,
Colca Jerry R
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.822.2
Subject(s) - chemistry , metabolite , chromatography , elution , diastereomer , active metabolite , stereochemistry , biochemistry
The objective of this study was to determine the stereochemistry of the carbonyl reduction of MSDC‐0602 in human, monkey and rat plasma using a validated LC‐MS/MS analytical method developed for the analysis of the four diastereomers of the major MSDC‐0602 reduction product, MSDC‐0597. The R‐ and S‐diastereomers of MSDC‐0597 have different in vitro binding affinities for mTOT and significantly different abilities to activate PPARγ, which has been implicated as the cause of the side effects of PPARγ insulin‐sensitizers. It is thus important to determine the stereochemistry of the major pharmacologically active metabolite of MSDC‐0602, MSDC‐0597, particularly with respect to its potential to have off target activity to activate PPARγ. A supported liquid extraction (SLE) procedure using either 100 μL or 25 μL (rat) of plasma was used for the analysis with the analytes eluted with methyl tert‐butyl ether (MTBE). The eluate was evaporated and the residue taken up in acetonitrile: water for injection on a Diacel CHIRALPAK® IA column. Analytes were eluted by isocratic chromatography using acetonitrile:methanol:2‐propanol:water, 67:12:18:3, v:v:v:v) at 50°C and the column effluent was monitored by negative ESI MS on SCIEX API 4000 or API 5500 instruments with an Analyst data system. Selected plasma samples were assayed from a human repeated dose study (Day 1 at 0, 4 and 24 hr, and Day 7 at 4 and 24 hr), a monkey repeated dose study (Day 1 at 0, 4 and 24 hr, and Day 182 at 4 and 24 hr), and a rat repeated dose study (Day 1 at 0, 4 and 24 hr, and Day 181 at 4 and 24 hr). No clinically significant gender differences in diastereomer percentages were apparent in any species. Overall mean R‐MSDC‐0597 concentrations in human, monkey and rat were 87.0±9.1%, 93.9±1.8% and 67.3±10.0%, respectively, of total MSDC‐0597. Overall mean R‐MSDC‐0597 percentages at 24 hr post‐dose were modestly lower than at 4 hr post‐dose in rat and human, but not in monkey. Owing to the more than ten‐fold lower in vitro ability of R‐MSDC‐0597 to bind to activate PPARγ than pioglitazone (ACTOS™), and its higher in vitro binding affinity for mTOT than pioglitazone, it is expected that MSDC‐0602 will have a better therapeutic ratio than pioglitazone in the treatment of NASH.