Synthesis and Preclinical Characterization of LY3154885, a Human Dopamine D1 Receptor Positive Allosteric Modulator with an Improved Nonclinical Drug–Drug Interaction Risk Profile

Results from recently completed clinical
studies suggest the dopamine
D1 receptor positive allosteric modulator (PAM) mevidalen (1) could offer unique value for lewy body dementia (LBD) patients.
In nonclinical assessments, 1 was mainly eliminated by
CYP3A4-mediated metabolism, therefore at the risk of being a victim
of drug–drug interactions (DDI) with CYP3A4 inhibitors and
inducers. An effort was initiated to identify a new D1 PAM with an
improved DDI risk profile. While attempts to introduce additional
metabolic pathways mediated by other CYP isoforms failed to provide
molecules with an acceptable profile, we discovered that the relative
contribution of CYP-mediated oxidation and UGT-mediated conjugation
could be tuned to reduce the CYP3A4-mediated victim DDI risk. We have
identified LY3154885 (5), a D1 PAM that possesses similar
in vitro and in vivo pharmacologic properties as 1, but
is metabolized mainly by UGT, predicting it could potentially offer
lower victim DDI risk in clinic.