Smith Sean M, Toolan Dawn, Kandebo Monika, Vardigan Joshua, Raheem Izzat, Layton Mark E, Kern Jeffrey C, Cox Christopher, Gantert Liza, Riffel Kerry, Hostetler Eric, Uslaner Jason M
Merck & Co, Inc, Rahway, New Jersey.
Merck & Co, Inc, Rahway, New Jersey.
J Pharmacol Exp Ther. 2025 Jan;392(1):100047. doi: 10.1124/jpet.124.002347. Epub 2024 Nov 26.
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 subnanomolar potency on the PDE10A enzyme and has excellent pharmaceutical properties. Oral administration of MK-8189 significantly increased cyclic guanosine monophosphate and phospho glutamate receptor 1 in rat striatal tissues. Activation of the dopamine D1 direct and D2 indirect pathways was demonstrated by detecting significant elevation of mRNA encoding substance P and enkephalin after MK-8189 administration. The PDE10A tracer [H]MK-8193 was used to determine the PDE10A enzyme occupancy (EO) required for efficacy in behavioral models. In the rat-conditioned avoidance responding assay, MK-8189 significantly decreased avoidance behavior at PDE10A EO greater than ∼48%. MK-8189 significantly reversed an MK-801-induced deficit in prepulse inhibition at PDE10A EO of ∼47% and higher. Target engagement of MK-8189 in rhesus monkeys was examined with [C]MK-8193 in positron emission tomography studies, and plasma concentrations of 127 nM MK-8189 yielded ∼50% EO in the striatum. The impact of MK-8189 on cognitive symptoms was evaluated using the objective retrieval task in rhesus monkeys. MK-8189 significantly attenuated a ketamine-induced deficit in object retrieval performance at exposure that yielded ∼29% PDE10A EO. These findings demonstrate the robust impact of MK-8189 on striatal signaling and efficacy in preclinical models of symptoms associated with schizophrenia. Data from these studies were used to establish the relationship between preclinical efficacy, plasma exposures, and PDE10A EO to guide dose selection of MK-8189 in clinical studies. SIGNIFICANCE STATEMENT: We describe the primary pharmacology of MK-8189, a phosphodiesterase 10A (PDE10A) inhibitor under evaluation for the treatment of schizophrenia. We report efficacy in preclinical models that have been used to characterize other PDE10A inhibitors and atypical antipsychotics. The PDE10A occupancy achieved by MK-8189 in behavioral studies was used to support dose selection in clinical trials. This work provides evidence to support exploration of higher levels of PDE10A occupancy in clinical trials to determine if this translates to improved efficacy in patients.
MK-8189是一种新型磷酸二酯酶10A（PDE10A）抑制剂，目前正在进行临床研究以评估其用于治疗精神分裂症的效果。PDE10A是一种环核苷酸磷酸二酯酶，在纹状体的中等棘状神经元中高度表达。MK-8189对PDE10A酶表现出亚纳摩尔级别的效力，并具有优异的药学性质。口服MK-8189可显著增加大鼠纹状体组织中的环磷酸鸟苷和磷酸化谷氨酸受体1。通过检测MK-8189给药后编码P物质和脑啡肽的mRNA显著升高，证实了多巴胺D1直接通路和D2间接通路的激活。PDE10A示踪剂[H]MK-8193用于确定行为模型中产生疗效所需的PDE10A酶占有率（EO）。在大鼠条件性回避反应试验中，当PDE10A EO大于约48%时，MK-8189可显著降低回避行为。在PDE10A EO为约47%及更高时，MK-8189可显著逆转MK-801诱导的前脉冲抑制缺陷。在正电子发射断层扫描研究中，用[C]MK-8193检测了MK-8189在恒河猴体内的靶点结合情况，血浆浓度为127 nM的MK-8189在纹状体中产生了约50%的EO。使用恒河猴的客观检索任务评估了MK-8189对认知症状的影响。在暴露时产生约29%的PDE10A EO的情况下，MK-8189可显著减轻氯胺酮诱导的物体检索性能缺陷。这些发现证明了MK-8189对纹状体信号传导的强大影响以及在与精神分裂症相关症状的临床前模型中的疗效。这些研究的数据用于建立临床前疗效、血浆暴露和PDE10A EO之间的关系，以指导MK-8189在临床研究中的剂量选择。重要声明：我们描述了MK-8189的主要药理学特性，它是一种正在评估用于治疗精神分裂症的磷酸二酯酶10A（PDE10A）抑制剂。我们报告了其在已用于表征其他PDE10A抑制剂和非典型抗精神病药物的临床前模型中的疗效。MK-8189在行为研究中实现的PDE10A占有率用于支持临床试验中的剂量选择。这项工作提供了证据，以支持在临床试验中探索更高水平的PDE10A占有率，以确定这是否能转化为患者疗效的改善。
