2. Academic Validation
  3. 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

  • J Med Chem. 2017 Oct 26;60(20):8369-8384. doi: 10.1021/acs.jmedchem.7b00746.
Keith F McDaniel 1,  Le Wang 1,  Todd Soltwedel 1,  Steven D Fidanze 1,  Lisa A Hasvold 1,  Dachun Liu 1,  Robert A Mantei 1,  John K Pratt 1,  George S Sheppard 1,  Mai H Bui 1,  Emily J Faivre 1,  Xiaoli Huang 1,  Leiming Li 1,  Xiaoyu Lin 1,  Rongqi Wang 1,  Scott E Warder 1,  Denise Wilcox 1,  Daniel H Albert 1,  Terrance J Magoc 1,  Ganesh Rajaraman 1,  Chang H Park 1,  Charles W Hutchins 1,  Jianwei J Shen 1,  Rohinton P Edalji 1,  Chaohong C Sun 1,  Ruth Martin 1,  Wenqing Gao 1,  Shekman Wong 1,  Guowei Fang 1,  Steven W Elmore 1,  Yu Shen 1,  Warren M Kati 1
Affiliations

Affiliation

  • 1 Oncology Discovery, AbbVie Inc. , 1 North Waukegan Rd., North Chicago, Illinois 60064, United States.
PMID: 28949521 DOI: 10.1021/acs.jmedchem.7b00746
Abstract

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.

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