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
文摘
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鈥揳ctivity 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>49b> achieved substantial tumor regression in an NPM-ALK driven murine tumor xenograft model when dosed qd. Compounds <b>36b> and <b>49b> show favorable potency and PK characteristics in preclinical species indicative of suitability for further development.