A Strategy to Minimize Reactive Metabolite Formation: Discovery of (S)-4-(1-Cyclopropyl-2-methoxyethyl)-6-[6-(difluoromethoxy)-2, 5-dimethylpyridin-3-ylamino]-5-oxo …

…, JA Deskus, VM Vrudhula, S Pan, JL Ditta…

Index: Hartz, Richard A.; Ahuja, Vijay T.; Zhuo, Xiaoliang; Mattson, Ronald J.; Denhart, Derek J.; Deskus, Jeffrey A.; Vrudhula, Vivekananda M.; Pan, Senliang; Ditta, Jonathan L.; Shu, Yue-Zhong; Grace, James E.; Lentz, Kimberley A.; Lelas, Snjezana; Li, Yu-Wen; Molski, Thaddeus F.; Krishnananthan, Subramaniam; Wong, Henry; Qian-Cutrone, Jingfang; Schartman, Richard; Denton, Rex; Lodge, Nicholas J.; Zaczek, Robert; Macor, John E.; Bronson, Joanne J. Journal of Medicinal Chemistry, 2009 , vol. 52, # 23 p. 7653 - 7668

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Citation Number: 38

Abstract

Detailed metabolic characterization of 8, an earlier lead pyrazinone-based corticotropin- releasing factor-1 (CRF1) receptor antagonist, revealed that this compound formed significant levels of reactive metabolites, as measured by in vivo and in vitro biotransformation studies. This was of particular concern due to the body of evidence suggesting that reactive metabolites may be involved in idiosyncratic drug reactions. ...