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Late-Stage Functionalization for the Optimization of Reversible BTK Inhibitors.

Authors :
Tyagarajan, Sriram
Guiadeen, Deodial
Streckfuss, Eric
Gao, Xiaolei
Buevich, Alexei V.
Doss, George
Liu, Jian
Vachal, Petr
Krska, Shane W.
Source :
Synlett; Aug2022, Vol. 33 Issue 13, p1259-1265, 7p
Publication Year :
2022

Abstract

Late-stage functionalization (LSF) enables medicinal chemists to quickly explore structure–activity relationships (SAR) of novel analogues derived from a fully elaborated parent structure. Using several known C–H functionalization chemistries, we have systematically applied the LSF strategy to modify different regions of a Bruton's tyrosine kinase (BTK) reversible inhibitor lead series. This approach allowed for broad SAR exploration across several key subunits of the molecule at positions that were previously difficult to explore with traditional synthesis, providing analogues with high potency and improved pharmacokinetic properties. This case study illustrates both the promise and the challenges associated with applying LSF to complex lead molecules. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
09365214
Volume :
33
Issue :
13
Database :
Complementary Index
Journal :
Synlett
Publication Type :
Academic Journal
Accession number :
158209289
Full Text :
https://doi.org/10.1055/s-0040-1719923