Abstract
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.
MeSH terms
-
Administration, Oral
-
Anaplastic Lymphoma Kinase
-
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
Substances
-
Antineoplastic Agents
-
Imidazoles
-
Protein Kinase Inhibitors
-
ALK protein, human
-
Alk protein, rat
-
Anaplastic Lymphoma Kinase
-
Receptor Protein-Tyrosine Kinases