Discovery and Lead Optimization of Atropisomer D1 Agonists with Reduced Desensitization

The discovery of D1 subtype-selective
agonists with drug-like properties
has been an enduring challenge for the greater part of 40 years. All
known D1-selective agonists are catecholamines that bring about receptor
desensitization and undergo rapid metabolism, thus limiting their
utility as a therapeutic for chronic illness such as schizophrenia
and Parkinson’s disease. Our high-throughput screening efforts
on D1 yielded a single non-catecholamine hit PF-4211 (6) that was developed into a series of potent D1 receptor agonist
leads with high oral bioavailability and CNS penetration. An important
structural feature of this series is the locked biaryl ring system
resulting in atropisomerism. Disclosed herein is a summary of our
hit-to-lead efforts on this series of D1 activators culminating in
the discovery of atropisomer 31 (PF-06256142), a potent
and selective orthosteric agonist of the D1 receptor that has reduced
receptor desensitization relative to dopamine and other catechol-containing
agonists.