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Article 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 profile. This work led to the identification of a potent BET inhibitor, 2-{8-fluoro-3-[4-(H)methyl-1-methyl-1-1,2,3-triazol-5-yl]-5-[()-(oxan-4-yl)(phenyl)methyl]-5-pyrido[3,2-]indol-7-yl}propan-2-ol (), which demonstrated reduced clearance and an improved pharmacokinetic (PK) profile across preclinical species. Importantly, no major metabolite was observed when was incubated with human hepatocytes (hHEP) for 2 h. This study culminated with the evaluation of in a mouse triple-negative breast cancer (TNBC) tumor model where it demonstrated robust efficacy at low doses.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9290009 | PMC |
| http://dx.doi.org/10.1021/acsmedchemlett.2c00219 | DOI Listing |
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