Discovery of MK-8189, a Highly Potent and Selective PDE10A Inhibitor for the Treatment of Schizophrenia

Phosphodiesterases (PDEs), enzymes that hydrolyze cAMP and cGMP, are crucial for neuronal signaling. PDE10A, highly expressed in the striatum, is implicated in the pathophysiology of schizophrenia, a debilitating disorder characterized by positive, negative, and cognitive symptoms. Current standard-of-care treatments, atypical antipsychotics, lack efficacy against negative and cognitive symptoms and have significant side effects. Preclinical studies suggest that PDE10A inhibitors could improve these limitations. This article describes the identification and preclinical development of an oral PDE10A inhibitor for clinical evaluation.

The introduction cites several papers supporting the role of PDE10A in striatal signaling and schizophrenia. Studies highlight the potential of PDE10A inhibition to restore impaired striatal output and improve symptoms, particularly positive symptoms, cognition, and addressing limitations of current therapies. The existing literature points towards a need for new treatments with improved efficacy and reduced side effects compared to atypical antipsychotics.

The research employed a multi-step approach beginning with a fragment screen identifying a 2-chloro-3-methyl pyrimidine (compound 1) as a PDE10A inhibitor. Rational design, guided by crystal structures, improved potency to picomolar levels (compound 2). However, compound 2 exhibited poor pharmacokinetic properties (low bioavailability, high clearance), low solubility, hERG activity, CYP inhibition, and PXR activation. Subsequent optimization focused on improving these properties. Two parallel strategies were pursued: 1) replacing the pyrimidine core with bicyclic systems (e.g., Pyp-1), which improved passive permeability and reduced P-gp substrate activity; and 2) modifying the monocyclic heteroaryl core, exploring different isomeric pyridines, quinolines, and naphthyridines (compounds 4-12), leading to improvements in solubility, CYP inhibition, and PK profiles. The team ultimately synthesized an isomeric pyrimidine series (compounds 13-18) exhibiting a superior balance of potency, selectivity, solubility, and pharmacokinetic parameters. Detailed synthetic schemes and characterization data are provided for key intermediates and final compounds. In vitro pharmacology, including PDE selectivity assays, surface plasmon resonance analysis, and a fluorescence polarization assay to measure cAMP hydrolysis inhibition, was conducted to evaluate the potency and selectivity of the optimized compounds. In vivo pharmacokinetics studies in rats and rhesus monkeys were carried out to assess bioavailability, clearance, and distribution. Ex vivo occupancy studies in rats, using [3H]MK-8193 as a tracer, determined PDE10A target engagement. Rodent behavioral assays (MK-801-induced hyperlocomotion and novel object recognition) evaluated the efficacy of compound 18 (MK-8189) in models of psychosis and cognitive impairment. Finally, in vitro safety and off-target profiling was performed.

Optimization yielded MK-8189 (compound 18), a highly potent and selective PDE10A inhibitor (functional Ki = 0.029 nM, >500,000-fold selectivity over other PDEs). MK-8189 displayed excellent physicochemical properties: high solubility (167 μM at pH 7), low molecular weight (382), and good lipophilicity (LogD = 2.1). In vivo, MK-8189 exhibited moderate clearance and low volume of distribution in rats and monkeys, resulting in a half-life of approximately 4-5 hours and oral bioavailability of 41-46%. It lacked significant CYP inhibition or PXR activation. In vivo enzyme occupancy studies demonstrated high PDE10A target engagement in the rat striatum. MK-8189 showed efficacy in rodent models of psychosis (MK-801-induced hyperlocomotion) and cognitive impairment (novel object recognition), with efficacy observed at approximately 25-29% enzyme occupancy. The compound also demonstrated a favorable tolerability profile in rats, lacking effects on prolactin levels and exhibiting a wide therapeutic window compared to atypical antipsychotics. Crystallographic analysis revealed specific interactions of MK-8189 within the PDE10A active site, including hydrogen bonds and π-stacking interactions.

The successful development of MK-8189 addresses the limitations of earlier PDE10A inhibitors. The improved physicochemical properties and pharmacokinetic profile, along with its potent and selective activity, make MK-8189 a promising candidate for treating schizophrenia. The in vivo efficacy data in rodent models, showing activity in both psychosis and cognition models at similar levels of target engagement, supports the clinical development of MK-8189 as a potential treatment for the full spectrum of schizophrenia symptoms. The favorable safety profile further strengthens this prospect. The achievement of high PDE10A occupancy in clinical trials allows for a more thorough examination of the PDE10A mechanism of action compared to earlier clinical trials.

MK-8189 (compound 18) is a potent and highly selective PDE10A inhibitor successfully advanced to Phase 2b clinical development for schizophrenia. Optimization addressed initial liabilities of an early pyrimidine series, resulting in improved physicochemical properties, pharmacokinetics, and a favorable safety profile. Preclinical data demonstrates efficacy in relevant animal models, supporting the potential of MK-8189 as a novel therapeutic for this debilitating disorder. Further clinical studies will determine the ultimate therapeutic utility of MK-8189 in treating schizophrenia.

The study primarily relies on preclinical data in rodent models. While these models offer valuable insights, the translation to human efficacy and safety requires further clinical investigation. The identification of somatostatin receptor type 2 (SSTR2) as a potential off-target warrants monitoring in clinical studies. The relatively weak substrate nature of MK-8189 towards rat P-gp (though full occupancy was achieved) should be considered in human studies.