1 research outputs found
Discovery of Benzotriazolo[4,3‑<i>d</i>][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains
Inhibition of the bromodomains of
the BET family, of which BRD4 is a member, has been shown to decrease
myc and interleukin (IL) 6 <i>in vivo</i>, markers that
are of therapeutic relevance to cancer and inflammatory disease, respectively.
Herein we report substituted benzo[<i>b</i>]isoxazolo[4,5-<i>d</i>]azepines and benzotriazolo[4,3-<i>d</i>][1,4]diazepines
as fragment-derived novel inhibitors of the bromodomain of BRD4. Compounds
from these series were potent and selective in cells, and subsequent
optimization of microsomal stability yielded representatives that
demonstrated dose- and time-dependent reduction of plasma IL-6 in
mice