MK-8189 has excellent PDE10A potency, PDE selectivity, pharmaceutical properties, ancillary profile, and oral PK in pre-clinical species. In vivo studies in rodents demonstrate PDE10A target engagement and efficacy in models of psychosis and cognition following oral administration.

2023年12月6日 · 临床药物侯选物mk-8189（化合物18）的优化过程 精神分裂症是一种复杂的精神类疾病，对社会危害性极大。 目前临床使用的精神分裂症治疗药物均以多巴胺受体和血清素受体为靶点，这些药物常常伴随着极大的副作用。

MK-8189 is a selective phosphodiesterase 10A inhibitor being developed for schizophrenia. It is developed by Merck in collaboration with Royalty Pharma. [1] [2] [3] [4]

PDE10A inhibitors increase cyclic nucleotides in striatal neurons, thereby mimicking the effects of dopamine receptor D2 antagonists and D1 agonists. We evaluated the PDE10A inhibitor MK-8189 for treating schizophrenia.

2023年1月26日 · Herein we describe the discovery of an isomeric pyrimidine series that addresses the liabilities seen with earlier compounds and resulted in the invention of compound 18 (MK-8189), which is currently in Phase 2b clinical development for the treatment of …

The purpose of this study is to evaluate the efficacy and safety of MK-8189 at a range of doses (8 mg, 16 mg, and 24 mg once daily) in adult participants who have an acute episode of schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders 5th Edition (DSM-5) criteria.

临床前研究表明，pde10a抑制剂有可能缓解多巴胺能和谷氨酸能功能障碍，表明mk-8189除了精神病症状外，还可能对认知障碍具广谱活性。mk-8189已在精神分裂症患者中完成多项1期试验，在全球正在进行2期临床。

2024年8月1日 · MK-8189 is a potent and highly selective PDE10A inhibitor that was shown to be efficacious in preclinical assays predictive of antipsychotic activity at doses producing at least 30–40 % enzyme occupancy, with greater effects on pathway activation at even higher levels of inhibition (Layton et al., 2023; Smith et al., 2022). MK-8189 was ...

MK-8189 is a novel phosphodiesterase 10A (PDE10A) inhibitor being evaluated in clinical studies for the treatment of schizophrenia. PDE10A is a cyclic nucleotide phosphodiesterase enzyme highly expressed in medium spiny neurons of the striatum. MK-8189 exhibits sub-nanomolar potency on the PDE10A en …

2023年9月21日 · MK-8189 is a selective inhibitor of phosphodiesterase 10A (PDE10A). This enzyme catalyzes the breakdown of second messengers cGMP and cAMP. PDE10A is abundantly expressed in the striatum in the human brain, and not in other tissues.