Novel Autotaxin Inhibitors for the Treatment of Osteoarthritis Pain: Lead Optimization via Structure-Based Drug Design

In an effort to develop a novel therapeutic
agent aimed at addressing
the unmet need of patients with osteoarthritis pain, we set out to
develop an inhibitor for autotaxin with excellent potency and physical
properties to allow for the clinical investigation of autotaxin-induced
nociceptive and neuropathic pain. An initial hit identification campaign
led to an aminopyrimidine series with an autotaxin IC50 of 500 nM. X-ray crystallography enabled the optimization to a lead
compound that demonstrated favorable potency (IC50 = 2
nM), PK properties, and a robust PK/PD relationship.