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...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2012-07, Vol.55 (14), p.6523-6540
Main Authors: Lewis, Richard T, Bode, Christiane M, Choquette, Deborah M, Potashman, Michele, Romero, Karina, Stellwagen, John C, Teffera, Yohannes, Moore, Earl, Whittington, Douglas A, Chen, Hao, Epstein, Linda F, Emkey, Renee, Andrews, Paul S, Yu, Violeta L, Saffran, Douglas C, Xu, Man, Drew, Allison, Merkel, Patricia, Szilvassy, Steven, Brake, Rachael L
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Antineoplastic Agents - chemistry
Antineoplastic Agents - metabolism
Antineoplastic Agents - pharmacokinetics
Antineoplastic Agents - pharmacology
Biological Availability
Cell Line, Tumor
Drug Discovery
Drug Stability
Humans
Imidazoles - chemistry
Imidazoles - metabolism
Imidazoles - pharmacokinetics
Imidazoles - pharmacology
Inhibitory Concentration 50
Microsomes, Liver - metabolism
Models, Molecular
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - metabolism
Protein Kinase Inhibitors - pharmacokinetics
Protein Kinase Inhibitors - pharmacology
Protein Structure, Tertiary
Rats
Receptor Protein-Tyrosine Kinases - antagonists & inhibitors
Receptor Protein-Tyrosine Kinases - chemistry
Receptor Protein-Tyrosine Kinases - metabolism
Substrate Specificity
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Description
Summary: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 49 achieved substantial tumor regression in an NPM-ALK driven murine tumor xenograft model when dosed qd. Compounds 36 and 49 show favorable potency and PK characteristics in preclinical species indicative of suitability for further development.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm3005866