4 research outputs found
Discovery of 4‑{4-[(3<i>R</i>)‑3-Methylmorpholin-4-yl]-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-2-yl}‑1<i>H</i>‑indole (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
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Novel macrocyclic HCV NS3 protease inhibitors derived from a-amino cyclic boronates
A novel series of P2-P4 macrocyclic HCV NS3/4A protease inhibitors with a-amino cyclic boronates as warheads at the P1 site was designed and synthesized. When compared to their linear analogs, these macrocyclic inhibitors exhibited a remarkable improvement in cell-based replicon activities, with compounds 9a and 9e reaching sub-micromolar potency in replicon assay. The SAR around a-amino cyclic boronates clearly established the influence of ring size, chirality and of the substitution pattern. Furthermore, X-ray structure of the co-crystal of inhibitor 9a and NS3 protease revealed that Ser-139 in the enzyme active site traps boron in the warhead region of 9a, thus establishing its mode of action
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Synthesis and evaluation of novel a-amino cyclic boronates as inhibitors of HCV NS3 protease
We have designed and synthesized a novel series of alpha-amino cyclic boronates and incorporated them successfully in several acyclic templates at the P1 position. These compounds are inhibitors of the HCV NS3 serine protease, and structural studies show that they inhibit the NS3 protease by trapping the Ser-139 hydroxyl group in the active site. Synthetic methodologies and SARs of this series of compounds are described
Discovery of a Potent Boronic Acid Derived Inhibitor of the HCV RNA-Dependent RNA Polymerase
A boronic acid moiety was found to
be a critical pharmacophore for enhanced in vitro potency against
wild-type hepatitis C replicons and known clinical polymorphic and
resistant HCV mutant replicons. The synthesis, optimization, and structure–activity
relationships associated with inhibition of HCV replication in a subgenomic
replication system for a series of non-nucleoside boron-containing
HCV RNA-dependent RNA polymerase (NS5B) inhibitors are described.
A summary of the discovery of <b>3</b> (GSK5852), a molecule
which entered clinical trials in subjects infected with HCV in 2011,
is included