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 been implicated in increased cellular proliferation,
migration, survival, and angiogenesis; hence, ERK5 inhibition may
be an attractive approach for cancer treatment. However, the development
of selective ERK5 inhibitors has been challenging. Previously, we
described the development of a pyrrole carboxamide high-throughput
screening hit into a selective, submicromolar inhibitor of ERK5 kinase
activity. Improvement in the ERK5 potency was necessary for the identification
of a tool ERK5 inhibitor for target validation studies. Herein, we
describe the optimization of this series to identify nanomolar pyrrole
carboxamide inhibitors of ERK5 incorporating a basic center, which
suffered from poor oral bioavailability. Parallel optimization of
potency and in vitro pharmacokinetic parameters led
to the identification of a nonbasic pyrazole analogue with an optimal
balance of ERK5 inhibition and oral exposure.