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Publication Abstract from PubMed

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-((2)H3)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.

Development of BET Inhibitors as Potential Treatments for Cancer: Optimization of Pharmacokinetic Properties.,Hill MD, Fang H, Norris D, Delucca GV, Huang H, DeBenedetto M, Quesnelle C, Schmitz WD, Tokarski JS, Sheriff S, Yan C, Fanslau C, Haarhoff Z, Huang C, Kramer M, Madari S, Menard K, Monereau L, Morrison J, Raghavan N, Shields EE, Simmermacher-Mayer J, Sinz M, Tye CK, Westhouse R, Xie C, Zhang H, Zhang L, Zvyaga T, Lee F, Gavai AV, Degnan AP ACS Med Chem Lett. 2022 Jul 5;13(7):1165-1171. doi:, 10.1021/acsmedchemlett.2c00219. eCollection 2022 Jul 14. PMID:35859878^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.