2 research outputs found
Direct Reductive Amination of Aldehyde Bisulfite Adducts Induced by 2‑Picoline Borane: Application to the Synthesis of a DPP-IV Inhibitor
Aldehyde-bisulfite adducts dervied from unstable parent
aldehydes
were reductively alkylated in a direct fashion with a variety of amines.
This approach features the use of 2-picoline borane as the reducing
agent and a protic solvent for the reaction media and has been successfully
applied to the synthesis of a DPP-IV inhibitor and a variety of other
amines
Oxopyrido[2,3‑<i>d</i>]pyrimidines as Covalent L858R/T790M Mutant Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors
In nonsmall cell lung cancer (NSCLC),
the threonine<sup>790</sup>–methionine<sup>790</sup> (T790M)
point mutation of EGFR kinase
is one of the leading causes of acquired resistance to the first generation
tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib.
Herein, we describe the optimization of a series of 7-oxopyridoÂ[2,3-<i>d</i>]Âpyrimidinyl-derived irreversible inhibitors of EGFR kinase.
This led to the discovery of compound <b>24</b> which potently
inhibits gefitinib-resistant EGFR<sup>L858R,T790M</sup> with 100-fold
selectivity over wild-type EGFR. Compound <b>24</b> displays
strong antiproliferative activity against the H1975 nonsmall cell
lung cancer cell line, the first line mutant HCC827 cell line, and
promising antitumor activity in an EGFR<sup>L858R,T790M</sup> driven
H1975 xenograft model sparing the side effects associated with the
inhibition of wild-type EGFR