Journal of Medicinal Chemistry
Journal of Medicinal Chemistry
5 years ago

Discovery of N-(4-(2,4-Difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)ethanesulfonamide (ABBV-075/Mivebresib), a Potent and Orally Available Bromodomain and Extraterminal Domain (BET) Family Bromodomain Inhibitor

Discovery of N-(4-(2,4-Difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)ethanesulfonamide (ABBV-075/Mivebresib), a Potent and Orally Available Bromodomain and Extraterminal Domain (BET) Family Bromodomain Inhibitor
John K. Pratt, Le Wang, Terrance J. Magoc, Leiming Li, Guowei Fang, Jianwei J. Shen, Scott E. Warder, Keith F. McDaniel, Steven W. Elmore, Chaohong C. Sun, Steven D. Fidanze, Charles W. Hutchins, George S. Sheppard, Xiaoyu Lin, Ganesh Rajaraman, Wenqing Gao, Daniel H. Albert, Denise Wilcox, Mai H. Bui, Yu Shen, Rohinton P. Edalji, Dachun Liu, Lisa A. Hasvold, Shekman Wong, Robert A. Mantei, Warren M. Kati, Rongqi Wang, Todd Soltwedel, Ruth Martin, Chang H. Park, Emily J. Faivre, Xiaoli Huang
The development of bromodomain and extraterminal domain (BET) bromodomain inhibitors and their examination in clinical studies, particularly in oncology settings, has garnered substantial recent interest. An effort to generate novel BET bromodomain inhibitors with excellent potency and drug metabolism and pharmacokinetics (DMPK) properties was initiated based upon elaboration of a simple pyridone core. Efforts to develop a bidentate interaction with a critical asparagine residue resulted in the incorporation of a pyrrolopyridone core, which improved potency by 9–19-fold. Additional structure–activity relationship (SAR) efforts aimed both at increasing potency and improving pharmacokinetic properties led to the discovery of the clinical candidate 63 (ABBV-075/mivebresib), which demonstrates excellent potency in biochemical and cellular assays, advantageous exposures and half-life both in animal models and in humans, and in vivo efficacy in mouse models of cancer progression and inflammation.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00746

DOI: 10.1021/acs.jmedchem.7b00746

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