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J Med Chem. 2012 Feb 23;55(4):1698-705. doi: 10.1021/jm201565s. Epub 2012 Feb 9.

Rapid development of piperidine carboxamides as potent and selective anaplastic lymphoma kinase inhibitors.

Author information

1
Medicinal Chemistry Research Technologies, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.

Abstract

Piperidine carboxamide 1 was identified as a novel inhibitor of anaplastic lymphoma kinase (ALK enzyme assay IC(50) = 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.

PMID:
22263917
DOI:
10.1021/jm201565s
[Indexed for MEDLINE]

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