| Literature DB >> 35859878 |
Matthew D Hill1, Haiquan Fang2, Derek Norris3, George V Delucca3, Hong Huang2, Mikkel DeBenedetto2, Claude Quesnelle3, William D Schmitz3, John S Tokarski3, Steven Sheriff3, Chunhong Yan3, Caroline Fanslau3, Zuzana Haarhoff3, Christine Huang3, Melissa Kramer2, Shilpa Madari3, Krista Menard3, Laura Monereau3, John Morrison3, Nirmala Raghavan3, Eric E Shields2, Jean Simmermacher-Mayer2, Michael Sinz3, Ching Kim Tye3, Richard Westhouse3, Chunshan Xie3, Haiying Zhang3, Lisa Zhang3, Tatyana Zvyaga3, Francis Lee3, Ashvinikumar V Gavai3, Andrew P Degnan3.
Abstract
We describe the synthesis of triazole-containing carboline derivatives and their utility as bromodomain and extra-terminal (BET) inhibitors. A convergent synthetic route permitted the detailed investigation of deuteration and fluorination strategies to reduce clearance while maintaining a favorable in vitro profile. This work led to the identification of a potent BET inhibitor, 2-{8-fluoro-3-[4-(2H3)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-(oxan-4-yl)(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol (15), which demonstrated reduced clearance and an improved pharmacokinetic (PK) profile across preclinical species. Importantly, no major metabolite was observed when 15 was incubated with human hepatocytes (hHEP) for 2 h. This study culminated with the evaluation of 15 in a mouse triple-negative breast cancer (TNBC) tumor model where it demonstrated robust efficacy at low doses.Entities:
Year: 2022 PMID： 35859878 PMCID： PMC9290009 DOI： 10.1021/acsmedchemlett.2c00219
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.632