3 research outputs found
Synthesis of Azabicycles via Cascade Aza-Prins Reactions: Accessing the Indolizidine and Quinolizidine Cores
The first detailed studies of intramolecular
aza-Prins and aza-silyl-Prins
reactions, starting from acyclic materials, are reported. The methods
allow rapid and flexible access toward an array of [6,5] and [6,6]
aza-bicycles, which form the core skeletons of various alkaloids.
On the basis of our findings on the aza-Prins and aza-silyl-Prins
cyclizations, herein we present simple protocols for the intramolecular
preparation of the azabicyclic cores of the indolizidines and quinolizidines
using a one-pot cascade process of <i>N</i>-acyliminium
ion formation followed by aza-Prins cyclization and either elimination
or carbocation trapping. It is possible to introduce a range of different
substituents into the heterocycles through a judicial choice of Lewis
acid and solvent(s), with halo-, phenyl-, and amido-substituted azabicyclic
products all being accessed through these highly diastereoselective
processes
Discovery of 4ā{4-[(3<i>R</i>)ā3-Methylmorpholin-4-yl]-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-2-yl}ā1<i>H</i>āindole (AZ20): A Potent and Selective Inhibitor of ATR Protein Kinase with Monotherapy in Vivo Antitumor Activity
ATR
is an attractive new anticancer drug target whose inhibitors
have potential as chemo- or radiation sensitizers or as monotherapy
in tumors addicted to particular DNA-repair pathways. We describe
the discovery and synthesis of a series of sulfonylmorpholinopyrimidines
that show potent and selective ATR inhibition. Optimization from a
high quality screening hit within tight SAR space led to compound <b>6</b> (AZ20) which inhibits ATR immunoprecipitated from HeLa nuclear
extracts with an IC<sub>50</sub> of 5 nM and ATR mediated phosphorylation
of Chk1 in HT29 colorectal adenocarcinoma tumor cells with an IC<sub>50</sub> of 50 nM. Compound <b>6</b> potently inhibits the
growth of LoVo colorectal adenocarcinoma tumor cells in vitro and
has high free exposure in mouse following moderate oral doses. At
well tolerated doses <b>6</b> leads to significant growth inhibition
of LoVo xenografts grown in nude mice. Compound <b>6</b> is
a useful compound to explore ATR pharmacology in vivo
Discovery of a Potent and Selective EGFR Inhibitor (AZD9291) of Both Sensitizing and T790M Resistance Mutations That Spares the Wild Type Form of the Receptor
Epidermal growth factor receptor
(EGFR) inhibitors have been used clinically in the treatment of non-small-cell
lung cancer (NSCLC) patients harboring sensitizing (or activating)
mutations for a number of years. Despite encouraging clinical efficacy
with these agents, in many patients resistance develops leading to
disease progression. In most cases, this resistance is in the form
of the T790M mutation. In addition, EGFR wild type receptor inhibition
inherent with these agents can lead to dose limiting toxicities of
rash and diarrhea. We describe herein the evolution of an early, mutant
selective lead to the clinical candidate AZD9291, an irreversible
inhibitor of both EGFR sensitizing (EGFRm+) and T790M resistance mutations
with selectivity over the wild type form of the receptor. Following
observations of significant tumor inhibition in preclinical models,
the clinical candidate was administered clinically to patients with
T790M positive EGFR-TKI resistant NSCLC and early efficacy has been
observed, accompanied by an encouraging safety profile