Discovery and optimization of novel constrained pyrrolopyridone BET family inhibitors

  • Bioorg Med Chem Lett. 2018 Jun 1;28(10):1804-1810. doi: 10.1016/j.bmcl.2018.04.020.
Steven D Fidanze  1 ,  Dachun Liu  2 ,  Robert A Mantei  3 ,  Lisa A Hasvold  3 ,  John K Pratt  3 ,  George S Sheppard  3 ,  Le Wang  3 ,  James H Holms  3 ,  Yujia Dai  3 ,  Ana Aguirre  3 ,  Andrew Bogdan  3 ,  Justin D Dietrich  3 ,  Jasmina Marjanovic  3 ,  Chang H Park  3 ,  Charles W Hutchins  3 ,  Xiaoyu Lin  3 ,  Mai H Bui  3 ,  Xiaoli Huang  3 ,  Denise Wilcox  3 ,  Leiming Li  3 ,  Rongqi Wang  3 ,  Peter Kovar  3 ,  Terrance J Magoc  3 ,  Ganesh Rajaraman  3 ,  Daniel H Albert  3 ,  Yu Shen  3 ,  Warren M Kati  3 ,  Keith F McDaniel  3
Affiliations
  • 1. AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064, United States. Electronic address: [email protected].
  • 2. AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064, United States. Electronic address: [email protected].
  • 3. AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064, United States.
PMID: 29678460 DOI: 10.1016/j.bmcl.2018.04.020
Abstract

Novel conformationally constrained BET bromodomain inhibitors have been developed. These inhibitors were optimized in two similar, yet distinct chemical series, the 6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (A) and the 1-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (B). Each series demonstrated excellent activity in binding and cellular assays, and lead compounds from each series demonstrated significant efficacy in in vivo tumor xenograft models.