molecules of the month


oral PDE10A inhibitor

Ph. IIb for schizophrenia

from fragment screen + SBDD

J. Med. Chem., January 10, 2023

Merck, West Point, PA

MK-8189 chemical structure oral PDE10A inhibitor - Merck, West Point, PA
8 mins read

What is it? MK-8189 is a Ph. II clinical candidate for schizophrenia targeting PDE10A, a long-pursued but uncracked target for psychosis. With potentially better target engagement over prior molecules, it could become the first in the class to demonstrate efficacy in this challenging therapeutic area. The discovery and medicinal chemistry campaigns are also notable, featuring a nearly million-fold potency improvement from a fragment, while securing properties that enable durable CNS target engagement. Remarkably, the final candidate, MK-8189 is highly lipophilically efficient (LLE = 7.8) and has a similar overall ligand-binding efficiency to its starting fragment (LBE = 0.54 vs. LBE = 0.57 for 1). Toward a non-dopaminergic treatment for schizophrenia. Schizophrenia is a serious mental illness with a lifetime prevalence…

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