VU0467485/AZ13713945的发现：一种被评估为治疗精神分裂症临床前候选药物的代谢型谷氨酸受体正向变构调节剂
Discovery of VU0467485/AZ13713945: An M PAM Evaluated as a Preclinical Candidate for the Treatment of Schizophrenia.
作者信息
Wood Michael R, Noetzel Meredith J, Melancon Bruce J, Poslusney Michael S, Nance Kellie D, Hurtado Miguel A, Luscombe Vincent B, Weiner Rebecca L, Rodriguez Alice L, Lamsal Atin, Chang Sichen, Bubser Michael, Blobaum Anna L, Engers Darren W, Niswender Colleen M, Jones Carrie K, Brandon Nicholas J, Wood Michael W, Duggan Mark E, Conn P Jeffrey, Bridges Thomas M, Lindsley Craig W
机构信息
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine , Nashville, Tennessee 37232, United States.
出版信息
ACS Med Chem Lett. 2016 Dec 16;8(2):233-238. doi: 10.1021/acsmedchemlett.6b00461. eCollection 2017 Feb 9.
Abstract
Herein, we report the structure-activity relationships within a series of potent, selective, and orally bioavailable muscarinic acetylcholine receptor 4 (M) positive allosteric modulators (PAMs). Compound (VU0467485) possesses robust M PAM potency across species and efficacy in preclinical models of schizophrenia. Coupled with an attractive DMPK profile and suitable predicted human PK, (VU0467485) was evaluated as a preclinical development candidate.
摘要
在此，我们报告了一系列强效、选择性且口服生物可利用的毒蕈碱型乙酰胆碱受体4（M4）正向变构调节剂（PAMs）的构效关系。化合物（VU0467485）在各物种中均具有强大的M4 PAM活性，且在精神分裂症临床前模型中有效。结合吸引人的药物代谢动力学（DMPK）特征和合适的预测人体药代动力学（PK），（VU0467485）被评估为临床前开发候选药物。
相似文献
1
Discovery of VU0467485/AZ13713945: An M PAM Evaluated as a Preclinical Candidate for the Treatment of Schizophrenia.VU0467485/AZ13713945的发现：一种被评估为治疗精神分裂症临床前候选药物的代谢型谷氨酸受体正向变构调节剂
ACS Med Chem Lett. 2016 Dec 16;8(2):233-238. doi: 10.1021/acsmedchemlett.6b00461. eCollection 2017 Feb 9.
2
Synthesis and Preliminary Evaluation of C-Labeled VU0467485/AZ13713945 and Its Analogues for Imaging Muscarinic Acetylcholine Receptor Subtype 4.C-标记的 VU0467485/AZ13713945 及其类似物的合成及初步评价及其类似物用于成像毒蕈碱乙酰胆碱受体亚型 4。
ChemMedChem. 2019 Feb 5;14(3):303-309. doi: 10.1002/cmdc.201800710. Epub 2018 Dec 27.
3
Discovery of VU6016235: A Highly Selective, Orally Bioavailable, and Structurally Distinct Tricyclic M Muscarinic Acetylcholine Receptor Positive Allosteric Modulator (PAM).VU6016235的发现：一种高选择性、口服生物可利用且结构独特的三环M型毒蕈碱乙酰胆碱受体正变构调节剂（PAM）。
ACS Chem Neurosci. 2024 Sep 24;15(20):3744-54. doi: 10.1021/acschemneuro.4c00465.
4
Discovery of VU0409551/JNJ-46778212: An mGlu5 Positive Allosteric Modulator Clinical Candidate Targeting Schizophrenia.VU0409551/JNJ-46778212的发现：一种靶向精神分裂症的mGlu5正变构调节剂临床候选药物。
ACS Med Chem Lett. 2015 May 20;6(6):716-20. doi: 10.1021/acsmedchemlett.5b00181. eCollection 2015 Jun 11.
5
Optimization of M positive allosteric modulators (PAMs): The discovery of VU0476406, a non-human primate in vivo tool compound for translational pharmacology.M 阳性变构调节剂（PAMs）的优化：VU0476406 的发现，一种用于转化药理学的非人灵长类动物体内工具化合物。
Bioorg Med Chem Lett. 2017 Jun 1;27(11):2296-2301. doi: 10.1016/j.bmcl.2017.04.043. Epub 2017 Apr 13.
6
Challenges in the development of an M PAM preclinical candidate: The discovery, SAR, and in vivo characterization of a series of 3-aminoazetidine-derived amides.MPAM临床前候选药物开发中的挑战：一系列3-氨基氮杂环丁烷衍生酰胺的发现、构效关系及体内特性研究
Bioorg Med Chem Lett. 2017 Jul 1;27(13):2990-2995. doi: 10.1016/j.bmcl.2017.05.014. Epub 2017 May 6.
7
Discovery, Optimization, and Biological Characterization of 2,3,6-Trisubstituted Pyridine-Containing M Positive Allosteric Modulators.发现、优化及 2,3,6-三取代吡啶含 M 正变构调节剂的生物学特征。
ChemMedChem. 2019 May 6;14(9):943-951. doi: 10.1002/cmdc.201900088. Epub 2019 Mar 28.
8
Challenges in the development of an M PAM in vivo tool compound: The discovery of VU0467154 and unexpected DMPK profiles of close analogs.开发一种体内 M PAM 工具化合物的挑战：VU0467154 的发现及紧密类似物意外的药物代谢动力学特征。
Bioorg Med Chem Lett. 2017 Jan 15;27(2):171-175. doi: 10.1016/j.bmcl.2016.11.086. Epub 2016 Nov 30.
10
Cognitive enhancement and antipsychotic-like activity following repeated dosing with the selective M PAM VU0467154.反复给予选择性 M PAM VU0467154 后认知增强和类抗精神病活性。
Neuropharmacology. 2018 Jan;128:492-502. doi: 10.1016/j.neuropharm.2017.07.013. Epub 2017 Jul 17.
引用本文的文献
1
Discovery of Pre-Clinical Candidate /: A Highly Selective, Orally Bioavailable, and Structurally Distinct Tricyclic M Muscarinic Acetylcholine Receptor Positive Allosteric Modulator (PAM) with Robust In Vivo Efficacy.临床前候选药物的发现：一种高选择性、口服生物可利用且结构独特的三环M型毒蕈碱乙酰胆碱受体正向变构调节剂（PAM），具有强大的体内疗效。
ACS Chem Neurosci. 2025 Jun 4;16(11):2141-2162. doi: 10.1021/acschemneuro.5c00277. Epub 2025 May 26.
2
Discovery of VU6016235: A Highly Selective, Orally Bioavailable, and Structurally Distinct Tricyclic M Muscarinic Acetylcholine Receptor Positive Allosteric Modulator (PAM).VU6016235的发现：一种高选择性、口服生物可利用且结构独特的三环M型毒蕈碱乙酰胆碱受体正变构调节剂（PAM）。
ACS Chem Neurosci. 2024 Sep 24;15(20):3744-54. doi: 10.1021/acschemneuro.4c00465.
3
A golden age of muscarinic acetylcholine receptor modulation in neurological diseases.神经退行性疾病中毒蕈碱型乙酰胆碱受体调节的黄金时代。
Nat Rev Drug Discov. 2024 Oct;23(10):743-758. doi: 10.1038/s41573-024-01007-1. Epub 2024 Aug 14.
4
Discovery of VU6008677: A Structurally Distinct Tricyclic M Positive Allosteric Modulator with Improved CYP450 Profile.VU6008677的发现：一种结构独特的三环M型正变构调节剂，具有改善的细胞色素P450酶谱。
ACS Med Chem Lett. 2024 Jul 3;15(8):1358-1366. doi: 10.1021/acsmedchemlett.4c00249. eCollection 2024 Aug 8.
5
Imaging Cholinergic Receptors in the Brain by Positron Emission Tomography.正电子发射断层扫描技术对脑内胆碱能受体的成像。
J Med Chem. 2023 Aug 24;66(16):10889-10916. doi: 10.1021/acs.jmedchem.3c00573. Epub 2023 Aug 15.
6
Characterization of a Novel M4 PAM PET Radioligand [11C]PF06885190 in Nonhuman Primates (NHP).新型 M4 PAM PET 放射性配体[11C]PF06885190 在非人灵长类动物（NHP）中的特征。
Molecules. 2023 Jun 7;28(12):4612. doi: 10.3390/molecules28124612.
7
The pyridazine heterocycle in molecular recognition and drug discovery.哒嗪杂环在分子识别与药物发现中的应用
Med Chem Res. 2023 Mar 15:1-69. doi: 10.1007/s00044-023-03035-9.
8
Pharmacological hallmarks of allostery at the M4 muscarinic receptor elucidated through structure and dynamics.通过结构和动力学研究揭示 M4 毒蕈碱受体变构作用的药理学特征。
Elife. 2023 May 30;12:e83477. doi: 10.7554/eLife.83477.
9
Structure-activity relationship of pyrazol-4-yl-pyridine derivatives and identification of a radiofluorinated probe for imaging the muscarinic acetylcholine receptor M.吡唑-4-基吡啶衍生物的构效关系及用于成像毒蕈碱型乙酰胆碱受体M的放射性氟化探针的鉴定
Acta Pharm Sin B. 2023 Jan;13(1):213-226. doi: 10.1016/j.apsb.2022.07.008. Epub 2022 Jul 21.
10
Effects of acute and repeated administration of the selective M PAM VU0152099 on cocaine versus food choice in male rats.急性和重复给予选择性 M PAM VU0152099 对雄性大鼠可卡因与食物选择的影响。
Addict Biol. 2022 Mar;27(2):e13145. doi: 10.1111/adb.13145.
本文引用的文献
1
Challenges in the development of an M PAM in vivo tool compound: The discovery of VU0467154 and unexpected DMPK profiles of close analogs.开发一种体内 M PAM 工具化合物的挑战：VU0467154 的发现及紧密类似物意外的药物代谢动力学特征。
Bioorg Med Chem Lett. 2017 Jan 15;27(2):171-175. doi: 10.1016/j.bmcl.2016.11.086. Epub 2016 Nov 30.
2
Antipsychotic-like Effects of M4 Positive Allosteric Modulators Are Mediated by CB2 Receptor-Dependent Inhibition of Dopamine Release.M4 正变构调节剂的抗精神病样作用由 CB2 受体依赖性抑制多巴胺释放介导。
Neuron. 2016 Sep 21;91(6):1244-1252. doi: 10.1016/j.neuron.2016.08.017. Epub 2016 Sep 8.
3
Prefrontal Cortex-Mediated Impairments in a Genetic Model of NMDA Receptor Hypofunction Are Reversed by the Novel M PAM VU6004256.在NMDA受体功能减退的遗传模型中，前额叶皮质介导的损伤被新型M PAM VU6004256逆转。
ACS Chem Neurosci. 2016 Dec 21;7(12):1706-1716. doi: 10.1021/acschemneuro.6b00230. Epub 2016 Oct 5.
4
Discovery and optimization of a novel series of highly CNS penetrant M4 PAMs based on a 5,6-dimethyl-4-(piperidin-1-yl)thieno[2,3-d]pyrimidine core.基于5,6-二甲基-4-(哌啶-1-基)噻吩并[2,3-d]嘧啶核心的新型系列高中枢神经系统渗透性M4型正变构调节剂的发现与优化
Bioorg Med Chem Lett. 2016 Jul 1;26(13):3029-3033. doi: 10.1016/j.bmcl.2016.05.010. Epub 2016 May 5.
5
Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors.GPCR变构调节剂发现中的实用策略与概念：代谢型谷氨酸受体的最新进展
Chem Rev. 2016 Jun 8;116(11):6707-41. doi: 10.1021/acs.chemrev.5b00656. Epub 2016 Feb 16.
6
Discovery of VU0409551/JNJ-46778212: An mGlu5 Positive Allosteric Modulator Clinical Candidate Targeting Schizophrenia.VU0409551/JNJ-46778212的发现：一种靶向精神分裂症的mGlu5正变构调节剂临床候选药物。
ACS Med Chem Lett. 2015 May 20;6(6):716-20. doi: 10.1021/acsmedchemlett.5b00181. eCollection 2015 Jun 11.
7
Potentiation of M1 Muscarinic Receptor Reverses Plasticity Deficits and Negative and Cognitive Symptoms in a Schizophrenia Mouse Model.M1毒蕈碱受体增强可逆转精神分裂症小鼠模型中的可塑性缺陷、阴性症状和认知症状。
Neuropsychopharmacology. 2016 Jan;41(2):598-610. doi: 10.1038/npp.2015.189. Epub 2015 Jun 25.
8
Opportunities and challenges in the discovery of allosteric modulators of GPCRs for treating CNS disorders.发现用于治疗中枢神经系统疾病的GPCR变构调节剂的机遇与挑战。
Nat Rev Drug Discov. 2014 Sep;13(9):692-708. doi: 10.1038/nrd4308.
9
Selective activation of M4 muscarinic acetylcholine receptors reverses MK-801-induced behavioral impairments and enhances associative learning in rodents.M4毒蕈碱型乙酰胆碱受体的选择性激活可逆转MK-801诱导的行为障碍并增强啮齿动物的联想学习能力。
ACS Chem Neurosci. 2014 Oct 15;5(10):920-42. doi: 10.1021/cn500128b. Epub 2014 Aug 19.
10
Antipsychotic drug-like effects of the selective M4 muscarinic acetylcholine receptor positive allosteric modulator VU0152100.选择性M4毒蕈碱型乙酰胆碱受体正向变构调节剂VU0152100的抗精神病药物样作用
Neuropsychopharmacology. 2014 Jun;39(7):1578-93. doi: 10.1038/npp.2014.2. Epub 2014 Jan 20.
Zotero 插件