临床前候选药物VU6008055/AF98943：一种高选择性、口服生物利用度、结构独特的三环M4毒蕈碱乙酰胆碱受体阳性变构调节剂（PAM），具有强大的体内疗效。

IF 3.9 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

ACS Chemical Neuroscience Pub Date : 2025-06-04 Epub Date: 2025-05-26 DOI:10.1021/acschemneuro.5c00277

Julie L Engers, Sean R Bollinger, Alison R Gregro, Rory A Capstick, Paul K Spearing, Madeline F Long, James C Tarr, Katherine J Watson, Sichen Chang, Vincent B Luscombe, Alice L Rodriguez, Hyekyung P Cho, Aidong Qi, Colleen M Niswender, Michael Bubser, Robert W Gould, William Hudson Robb, Nellie Byun, John Gore, Carrie K Jones, Morten S Thomsen, Thomas M Bridges, Olivier Boutaud, P Jeffrey Conn, Darren W Engers, Craig W Lindsley, Kayla J Temple

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引用次数: 0

摘要

在此，我们报道了结构-活性关系，以开发具有改进药理性能的新型三环M4阳性变构调节剂支架。这项工作涉及通过“回接”策略修饰5-氨基-3,4-二甲基噻吩[2,3-c]吡啶-6-羧酰胺核心，以发现新的三环3,4-二甲基嘧啶[4',5':4,5]噻吩[2,3-c]吡啶核心。由此，VU6008055/AF98943被确定为临床前候选药物，对人和大鼠M4均表现出低纳摩尔效价。此外，VU6008055具有高脑渗透性，总体上具有优于先前报道的M4 PAMs的药理学和DMPK谱，并且在临床前模型中显示出抗精神病样活性的有效性。

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Discovery of Pre-Clinical Candidate VU6008055/AF98943: A Highly Selective, Orally Bioavailable, and Structurally Distinct Tricyclic M₄ Muscarinic Acetylcholine Receptor Positive Allosteric Modulator (PAM) with Robust In Vivo Efficacy.

Herein, we report the structure-activity relationship to develop novel tricyclic M₄ positive allosteric modulator scaffolds with improved pharmacological properties. This endeavor involved modifying a 5-amino-3,4-dimethylthieno[2,3-c]pyridazine-6-carboxamide core via a "tie-back" strategy to discover a novel tricyclic 3,4-dimethylpyrimido[4',5':4,5]thieno[2,3-c]pyridazine core. From this exercise, VU6008055/AF98943 was identified as a preclinical candidate, which displays low nanomolar potency against both human and rat M₄. Moreover, VU6008055 is highly brain penetrant, has an overall superior pharmacological and DMPK profile to previously reported M₄ PAMs, and demonstrates efficacy in preclinical models of antipsychotic-like activity.

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来源期刊

ACS Chemical Neuroscience BIOCHEMISTRY & MOLECULAR BIOLOGY-CHEMISTRY, MEDICINAL

CiteScore

9.20

自引率

4.00%

发文量

323

审稿时长

1 months

期刊介绍： ACS Chemical Neuroscience publishes high-quality research articles and reviews that showcase chemical, quantitative biological, biophysical and bioengineering approaches to the understanding of the nervous system and to the development of new treatments for neurological disorders. Research in the journal focuses on aspects of chemical neurobiology and bio-neurochemistry such as the following: Neurotransmitters and receptors Neuropharmaceuticals and therapeutics Neural development—Plasticity, and degeneration Chemical, physical, and computational methods in neuroscience Neuronal diseases—basis, detection, and treatment Mechanism of aging, learning, memory and behavior Pain and sensory processing Neurotoxins Neuroscience-inspired bioengineering Development of methods in chemical neurobiology Neuroimaging agents and technologies Animal models for central nervous system diseases Behavioral research