molecules of the month

Context. LY3154885 (Eli Lilly and Company) is an oral D1 modulator. Lilly recently completed several clinical trials with LY3154207 (mevidalen), the first D1 positive allosteric modulator (D1PAM) with published clinical data, in Parkinson’s disease (NCT02562768), sleep (NCT02603861), and lewy body dementia (LBD) (NCT03305809). In nonclinical studies, mevidalen was found to be mainly cleared by CYP3A4, creating a risk for it being a victim drug to DDIs when co-dosed with CYP3A4 inhibitors or inducers. LY3154885 was a backup compound to address this DDI risk, with metabolism shifted from CYP-mediated to predominantly UGT-mediated by changing the tertiary alcohol-bearing group to a pyrazole. The molecule was advanced to Ph. I, but terminated early due to a business decision. Mechanism of Action. The D1…