2 research outputs found
Rapid Development of Piperidine Carboxamides as Potent and Selective Anaplastic Lymphoma Kinase Inhibitors
Piperidine carboxamide <b>1</b> was identified
as a novel
inhibitor of anaplastic lymphoma kinase (ALK enzyme assay IC<sub>50</sub> = 0.174 μM) during high throughput screening, with selectivity
over the related kinase insulin-like growth factor-1 (IGF1R). The
X-ray cocrystal structure of <b>1</b> with the ALK kinase domain
revealed an unusual DFG-shifted conformation, allowing access to an
extended hydrophobic pocket. Structure–activity relationship
(SAR) studies were focused on the rapid parallel optimization of both
the right- and left-hand side of the molecule, culminating in molecules
with improved potency and selectivity over IGF1R
The Discovery and Optimization of a Novel Class of Potent, Selective, and Orally Bioavailable Anaplastic Lymphoma Kinase (ALK) Inhibitors with Potential Utility for the Treatment of Cancer
A class of 2-acyliminobenzimidazoles has been developed
as potent and selective inhibitors of anaplastic lymphoma kinase (ALK).
Structure based design facilitated the rapid development of structure–activity
relationships (SAR) and the optimization of kinase selectivity. Introduction
of an optimally placed polar substituent was key to solving issues
of metabolic stability and led to the development of potent, selective,
orally bioavailable ALK inhibitors. Compound <b>49</b> achieved
substantial tumor regression in an NPM-ALK driven murine tumor xenograft
model when dosed qd. Compounds <b>36</b> and <b>49</b> show favorable potency and PK characteristics in preclinical species
indicative of suitability for further development