Med Chem Paper of the Month – Jan/Feb 2023
This paper is a fine exhibition of multi-parameter optimisation that resulted in the candidate drug: MK-8189, currently undergoing phase II clinical trials for the treatment of schizophrenia.
Discovery of MK-8189, a Highly Potent and Selective PDE10A Inhibitor for the Treatment of Schizophrenia
Schizophrenia is a debilitating mental disorder with an estimated prevalence of ~0.5% in the US population. It is typically characterised by symptoms including: psychosis, hallucinations, cognitive impairment, amotivation and apathy. Dysfunctional striatal signalling is thought to be implicated in the pathophysiology of schizophrenia, phosphodiesterase-10A (PDE10A) is the enzyme thought to regulate this signalling pathway, and has emerged as a promising inhibition target that could lead to new medicines for this condition.
Investigators at Merck & Co., Inc. previously identified a simple dichloropyrimidine (1) during a fragment screening campaign as an efficient binder and micromolar inhibitor of PDE10A. Since the discovery of this initial hit compound, there has been an enormous amount of fragment-to-lead and lead optimisation work dedicated to addressing a host of PK and ADMET liabilities required in order to bring forward a candidate drug from this series. Early work identified the “western” ether-linked heterocycle as being important for PDE10A selectivity because of binding to the crucial Tyr683 residue found in this target. The trans-cyclopropane linker was important for metabolic stability. The “eastern” portion was optimised with safety indications in mind, resulting in a safe >15-fold reduction in hERG inhibition activity. In this paper, the final variable: the pyrimidine core, was considered to address liabilities surrounding CYP450 inhibition, PXR activation and rat pharmacokinetics. It is a fine exhibition of multi-parameter optimisation that resulted in the candidate drug: MK-8189, currently undergoing phase II clinical trials for the treatment of schizophrenia.