jm201565s_si_001.pdf (169.74 kB)

Rapid Development of Piperidine Carboxamides as Potent and Selective Anaplastic Lymphoma Kinase Inhibitors

Download (169.74 kB)
journal contribution
posted on 22.02.2016, 05:01 by Marian C. Bryan, Douglas A. Whittington, Elizabeth M. Doherty, James R. Falsey, Alan C. Cheng, Renee Emkey, Rachael L. Brake, Richard T. Lewis
Piperidine carboxamide 1 was identified as a novel inhibitor of anaplastic lymphoma kinase (ALK enzyme assay IC50 = 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 1 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.

History

Exports