Parallel Optimization of Potency and Pharmacokinetics Leading to the Discovery of a Pyrrole Carboxamide ERK5 Kinase Domain Inhibitor

The nonclassical extracellular signal-related kinase 5 (ERK5) mitogen-activated protein kinase pathway has beenimplicated in increased cellular proliferation, migration, survival, and angiogenesis; hence, ERK5 inhibition may be an attractiveapproach for cancer treatment. However, the development of selective ERK5 inhibitors has been challenging. Previously, wedescribed the development of a pyrrole carboxamide high-throughput screening hit into a selective, submicromolar inhibitor ofERK5 kinase activity. Improvement in the ERK5 potency was necessary for the identification of a tool ERK5 inhibitor for targetvalidation studies. Herein, we describe the optimization of this series to identify nanomolar pyrrole carboxamide inhibitors of ERK5incorporating a basic center, which suffered from poor oral bioavailability. Parallel optimization of potency andin vitropharmacokinetic parameters led to the identification of a nonbasic pyrazole analogue with an optimal balance of ERK5 inhibitionand oral exposure.