4 research outputs found
A Practical Synthesis of Indoles via a Pd-Catalyzed C–N Ring Formation
A method for the
synthesis of <i>N</i>-functionalized
C2-/C3-substituted indoles via Pd-catalyzed C–N bond coupling
of halo-aryl enamines is described. The general strategy utilizes
a variety of amines and β-keto esters which are elaborated into
halo-aryl enamines as latent precursors to indoles. The preferred
conditions comprising the RuPhos precatalyst and RuPhos in the presence
of NaOMe in 1,4-dioxane tolerate a variety of substituents and are
scalable for the construction of indoles in multigram quantities
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
Discovery, Design, and Optimization of Isoxazole Azepine BET Inhibitors
The identification of a novel series
of small molecule BET inhibitors is described. Using crystallographic
binding modes of an amino-isoxazole fragment and known BET inhibitors,
a structure-based drug design effort lead to a novel isoxazole azepine
scaffold. This scaffold showed good potency in biochemical and cellular
assays and oral activity in an in vivo model of BET inhibition
Fragment-Based Discovery of a Selective and Cell-Active Benzodiazepinone CBP/EP300 Bromodomain Inhibitor (CPI-637)
CBP and EP300 are highly homologous,
bromodomain-containing transcription
coactivators involved in numerous cellular pathways relevant to oncology.
As part of our effort to explore the potential therapeutic implications
of selectively targeting bromodomains, we set out to identify a CBP/EP300
bromodomain inhibitor that was potent both <i>in vitro</i> and in cellular target engagement assays and was selective over
the other members of the bromodomain family. Reported here is a series
of cell-potent and selective probes of the CBP/EP300 bromodomains,
derived from the fragment screening hit 4-methyl-1,3,4,5-tetrahydro-2<i>H</i>-benzo[<i>b</i>][1,4]diazepin-2-one