4 research outputs found
Discovery of Potent and Selective 8‑Fluorotriazolopyridine c‑Met Inhibitors
The overexpression of c-Met and/or
hepatocyte growth factor (HGF),
the amplification of the MET gene, and mutations in the c-Met kinase
domain can activate signaling pathways that contribute to cancer progression
by enabling tumor cell proliferation, survival, invasion, and metastasis.
Herein, we report the discovery of 8-fluorotriazolopyridines as inhibitors
of c-Met activity. Optimization of the 8-fluorotriazolopyridine scaffold
through the combination of structure-based drug design, SAR studies,
and metabolite identification provided potent (cellular IC<sub>50</sub> < 10 nM), selective inhibitors of c-Met with desirable pharmacokinetic
properties that demonstrate potent inhibition of HGF-mediated c-Met
phosphorylation in a mouse liver pharmacodynamic model
Discovery of (<i>R</i>)‑6-(1-(8-Fluoro-6-(1-methyl‑1<i>H</i>‑pyrazol-4-yl)-[1,2,4]triazolo[4,3‑<i>a</i>]pyridin-3-yl)ethyl)-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6<i>H</i>)‑one (AMG 337), a Potent and Selective Inhibitor of MET with High Unbound Target Coverage and Robust In Vivo Antitumor Activity
Deregulation
of the receptor tyrosine kinase mesenchymal epithelial
transition factor (MET) has been implicated in several human cancers
and is an attractive target for small molecule drug discovery. Herein,
we report the discovery of compound <b>23</b> (AMG 337), which
demonstrates nanomolar inhibition of MET kinase activity, desirable
preclinical pharmacokinetics, significant inhibition of MET phosphorylation
in mice, and robust tumor growth inhibition in a MET-dependent mouse
efficacy model
Sulfonamides as Selective Na<sub>V</sub>1.7 Inhibitors: Optimizing Potency, Pharmacokinetics, and Metabolic Properties to Obtain Atropisomeric Quinolinone (AM-0466) that Affords Robust in Vivo Activity
Because of its strong genetic validation,
Na<sub>V</sub>1.7 has
attracted significant interest as a target for the treatment of pain.
We have previously reported on a number of structurally distinct bicyclic
heteroarylsulfonamides as Na<sub>V</sub>1.7 inhibitors that demonstrate
high levels of selectivity over other Na<sub>V</sub> isoforms. Herein,
we report the discovery and optimization of a series of atropisomeric
quinolinone sulfonamide inhibitors [Bicyclic sulfonamide compounds as sodium channel inhibitors
and their preparation. WO 2014201206, 2014] of Na<sub>V</sub>1.7, which demonstrate nanomolar inhibition of
Na<sub>V</sub>1.7 and exhibit high levels of selectivity over other
sodium channel isoforms. After optimization of metabolic and pharmacokinetic
properties, including PXR activation, CYP2C9 inhibition, and CYP3A4
TDI, several compounds were advanced into in vivo target engagement
and efficacy models. When tested in mice, compound <b>39</b> (AM-0466) demonstrated robust pharmacodynamic activity in a Na<sub>V</sub>1.7-dependent model of histamine-induced pruritus (itch) and
additionally in a capsaicin-induced nociception model of pain without
any confounding effect in open-field activity
Sulfonamides as Selective Na<sub>V</sub>1.7 Inhibitors: Optimizing Potency, Pharmacokinetics, and Metabolic Properties to Obtain Atropisomeric Quinolinone (AM-0466) that Affords Robust in Vivo Activity
Because of its strong genetic validation,
Na<sub>V</sub>1.7 has
attracted significant interest as a target for the treatment of pain.
We have previously reported on a number of structurally distinct bicyclic
heteroarylsulfonamides as Na<sub>V</sub>1.7 inhibitors that demonstrate
high levels of selectivity over other Na<sub>V</sub> isoforms. Herein,
we report the discovery and optimization of a series of atropisomeric
quinolinone sulfonamide inhibitors [Bicyclic sulfonamide compounds as sodium channel inhibitors
and their preparation. WO 2014201206, 2014] of Na<sub>V</sub>1.7, which demonstrate nanomolar inhibition of
Na<sub>V</sub>1.7 and exhibit high levels of selectivity over other
sodium channel isoforms. After optimization of metabolic and pharmacokinetic
properties, including PXR activation, CYP2C9 inhibition, and CYP3A4
TDI, several compounds were advanced into in vivo target engagement
and efficacy models. When tested in mice, compound <b>39</b> (AM-0466) demonstrated robust pharmacodynamic activity in a Na<sub>V</sub>1.7-dependent model of histamine-induced pruritus (itch) and
additionally in a capsaicin-induced nociception model of pain without
any confounding effect in open-field activity