发现3-氨基吡啶甲酰胺作为代谢型谷氨酸受体亚型4（mGlu4）的正变构调节剂弹头，可实现中枢神经系统暴露及体内疗效。
Discovery of 3-aminopicolinamides as metabotropic glutamate receptor subtype 4 (mGlu4) positive allosteric modulator warheads engendering CNS exposure and in vivo efficacy.
作者信息
Gogliotti Rocco D, Engers Darren W, Garcia-Barrantes Pedro M, Panarese Joseph D, Gentry Patrick R, Blobaum Anna L, Morrison Ryan D, Daniels J Scott, Thompson Analisa D, Jones Carrie K, Conn P Jeffrey, Niswender Colleen M, Lindsley Craig W, Hopkins Corey R
机构信息
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
出版信息
Bioorg Med Chem Lett. 2016 Jun 15;26(12):2915-2919. doi: 10.1016/j.bmcl.2016.04.041. Epub 2016 Apr 19.
Abstract
This letter describes the further chemical optimization of the picolinamide-derived family of mGlu4 PAMs wherein we identified a 3-amino substituent to the picolinamide warhead that engendered potency, CNS penetration and in vivo efficacy. From this optimization campaign, VU0477886 emerged as a potent (EC50=95nM, 89% Glu Max) mGlu4 PAM with an attractive DMPK profile (brain:plasma Kp=1.3), rat CLp=4.0mL/min/kg, t1/2=3.7h) and robust efficacy in our standard preclinical Parkinson's disease model, haloperidol-induced catalepsy (HIC).
摘要
这封信描述了吡啶甲酰胺衍生的mGlu4 正变构调节剂家族的进一步化学优化，其中我们在吡啶甲酰胺弹头中确定了一个3-氨基取代基，该取代基带来了效力、中枢神经系统渗透性和体内疗效。通过这次优化，VU0477886成为一种强效的（EC50=95nM，89%的谷氨酸最大反应）mGlu4 正变构调节剂，具有吸引人的药物代谢动力学特性（脑：血浆分配系数Kp=1.3），大鼠肝清除率CLp=4.0mL/分钟/千克，半衰期t1/2=3.7小时），并且在我们标准的临床前帕金森病模型——氟哌啶醇诱导的僵住症（HIC）中具有强大的疗效。
相似文献
1
Discovery of 3-aminopicolinamides as metabotropic glutamate receptor subtype 4 (mGlu4) positive allosteric modulator warheads engendering CNS exposure and in vivo efficacy.发现3-氨基吡啶甲酰胺作为代谢型谷氨酸受体亚型4（mGlu4）的正变构调节剂弹头，可实现中枢神经系统暴露及体内疗效。
Bioorg Med Chem Lett. 2016 Jun 15;26(12):2915-2919. doi: 10.1016/j.bmcl.2016.04.041. Epub 2016 Apr 19.
2
Discovery and optimization of a novel CNS penetrant series of mGlu PAMs based on a 1,4-thiazepane core with in vivo efficacy in a preclinical Parkinsonian model.基于 1,4-噻唑烷核心发现并优化新型 CNS 穿透性 mGlu PAMs 系列化合物，在临床前帕金森模型中具有体内疗效。
Bioorg Med Chem Lett. 2021 Apr 1;37:127838. doi: 10.1016/j.bmcl.2021.127838. Epub 2021 Feb 5.
3
The discovery of VU0652957 (VU2957, Valiglurax): SAR and DMPK challenges en route to an mGlu PAM development candidate.VU0652957（VU2957，Valiglurax）的发现：在开发 mGlu PAM 开发候选药物过程中的 SAR 和 DMPK 挑战。
Bioorg Med Chem Lett. 2019 Jan 15;29(2):342-346. doi: 10.1016/j.bmcl.2018.10.050. Epub 2018 Nov 1.
4
Discovery, Structure-Activity Relationship, and Biological Characterization of a Novel Series of 6-((1 H-Pyrazolo[4,3- b]pyridin-3-yl)amino)-benzo[ d]isothiazole-3-carboxamides as Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 4 (mGlu).新型 6-((1 H-吡唑并[4,3- b]吡啶-3-基)氨基)苯并[ d]异噻唑-3-甲酰胺类代谢型谷氨酸受体 4(mGlu4)正变构调节剂的发现、构效关系及生物学特性研究。
J Med Chem. 2019 Jan 10;62(1):342-358. doi: 10.1021/acs.jmedchem.8b00994. Epub 2018 Oct 10.
5
Development and Antiparkinsonian Activity of VU0418506, a Selective Positive Allosteric Modulator of Metabotropic Glutamate Receptor 4 Homomers without Activity at mGlu2/4 Heteromers.代谢型谷氨酸受体4同聚体的选择性正变构调节剂VU0418506的研发及其抗帕金森病活性：VU0418506对代谢型谷氨酸受体2/4异聚体无活性
ACS Chem Neurosci. 2016 Sep 21;7(9):1201-11. doi: 10.1021/acschemneuro.6b00036. Epub 2016 Aug 5.
6
Lead optimization of the VU0486321 series of mGlu1 PAMs. Part 3. Engineering plasma stability by discovery and optimization of isoindolinone analogs.亲代谢型谷氨酸受体1 （mGlu1） 正变构调节剂（PAMs）VU0486321系列的先导化合物优化。第3部分。通过异吲哚啉酮类似物的发现与优化来设计血浆稳定性。
Bioorg Med Chem Lett. 2016 Apr 15;26(8):1869-72. doi: 10.1016/j.bmcl.2016.03.031. Epub 2016 Mar 10.
7
Discovery, synthesis, and structure-activity relationship development of a series of N-(4-acetamido)phenylpicolinamides as positive allosteric modulators of metabotropic glutamate receptor 4 (mGlu(4)) with CNS exposure in rats.发现、合成和结构活性关系研究一系列 N-(4-乙酰氨基)苯吡啶甲酰胺作为代谢型谷氨酸受体 4（mGlu(4)）的正别构调节剂，在大鼠中枢神经系统中具有暴露量。
J Med Chem. 2011 Feb 24;54(4):1106-10. doi: 10.1021/jm101271s. Epub 2011 Jan 19.
8
Discovery, Synthesis, and Preclinical Characterization of N-(3-Chloro-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine (VU0418506), a Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 (mGlu4).代谢型谷氨酸受体4（mGlu4）新型正变构调节剂N-（3-氯-4-氟苯基）-1H-吡唑并[4,3-b]吡啶-3-胺（VU0418506）的发现、合成及临床前特性研究
ACS Chem Neurosci. 2016 Sep 21;7(9):1192-200. doi: 10.1021/acschemneuro.6b00035. Epub 2016 May 3.
9
Re-exploration of the mGlu₁ PAM Ro 07-11401 scaffold: Discovery of analogs with improved CNS penetration despite steep SAR.对代谢型谷氨酸受体1（mGlu₁）的正变构调节剂（PAM）Ro 07-11401骨架的重新探索：尽管结构活性关系（SAR）很陡峭，但仍发现了具有改善的中枢神经系统（CNS）渗透性的类似物。
Bioorg Med Chem Lett. 2016 May 1;26(9):2289-92. doi: 10.1016/j.bmcl.2016.03.044. Epub 2016 Mar 14.
10
Synergy between L-DOPA and a novel positive allosteric modulator of metabotropic glutamate receptor 4: implications for Parkinson's disease treatment and dyskinesia.L-DOPA 与代谢型谷氨酸受体 4 的新型正变构调节剂的协同作用：对帕金森病治疗和运动障碍的影响。
Neuropharmacology. 2013 Mar;66:158-69. doi: 10.1016/j.neuropharm.2012.03.022. Epub 2012 Apr 3.
本文引用的文献
1
Discovery, Synthesis, and Preclinical Characterization of N-(3-Chloro-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine (VU0418506), a Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 (mGlu4).代谢型谷氨酸受体4（mGlu4）新型正变构调节剂N-（3-氯-4-氟苯基）-1H-吡唑并[4,3-b]吡啶-3-胺（VU0418506）的发现、合成及临床前特性研究
ACS Chem Neurosci. 2016 Sep 21;7(9):1192-200. doi: 10.1021/acschemneuro.6b00035. Epub 2016 May 3.
2
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.
3
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.
4
Recent progress on the identification of metabotropic glutamate 4 receptor ligands and their potential utility as CNS therapeutics.近期代谢型谷氨酸 4 受体配体鉴定的进展及其作为中枢神经系统治疗药物的潜在应用。
ACS Chem Neurosci. 2011 Aug 17;2(8):433-49. doi: 10.1021/cn200043e. Epub 2011 Jun 14.
5
The metabotropic glutamate receptor 4-positive allosteric modulator VU0364770 produces efficacy alone and in combination with L-DOPA or an adenosine 2A antagonist in preclinical rodent models of Parkinson's disease.代谢型谷氨酸受体 4 正变构调节剂 VU0364770 在帕金森病的临床前啮齿动物模型中单独使用以及与 L-DOPA 或腺苷 2A 拮抗剂联合使用都具有疗效。
J Pharmacol Exp Ther. 2012 Feb;340(2):404-21. doi: 10.1124/jpet.111.187443. Epub 2011 Nov 16.
6
Discovery, synthesis, and structure-activity relationship development of a series of N-4-(2,5-dioxopyrrolidin-1-yl)phenylpicolinamides (VU0400195, ML182): characterization of a novel positive allosteric modulator of the metabotropic glutamate receptor 4 (mGlu(4)) with oral efficacy in an antiparkinsonian animal model.发现、合成及一系列 N-4-(2,5-二氧代吡咯烷-1-基)吡啶甲酰胺（VU0400195，ML182）的结构-活性关系发展：一种新型代谢型谷氨酸受体 4（mGlu(4)）正变构调节剂的鉴定，其在抗帕金森病动物模型中具有口服疗效。
J Med Chem. 2011 Nov 10;54(21):7639-47. doi: 10.1021/jm200956q. Epub 2011 Oct 19.
7
Discovery, synthesis, and structure-activity relationship development of a series of N-(4-acetamido)phenylpicolinamides as positive allosteric modulators of metabotropic glutamate receptor 4 (mGlu(4)) with CNS exposure in rats.发现、合成和结构活性关系研究一系列 N-(4-乙酰氨基)苯吡啶甲酰胺作为代谢型谷氨酸受体 4（mGlu(4)）的正别构调节剂，在大鼠中枢神经系统中具有暴露量。
J Med Chem. 2011 Feb 24;54(4):1106-10. doi: 10.1021/jm101271s. Epub 2011 Jan 19.
8
Synthesis and SAR of novel, 4-(phenylsulfamoyl)phenylacetamide mGlu4 positive allosteric modulators (PAMs) identified by functional high-throughput screening (HTS).通过功能高通量筛选（HTS）鉴定的新型 4-（苯磺酰胺基）苯基乙酰胺 mGlu4 正变构调节剂（PAMs）的合成和 SAR。
Bioorg Med Chem Lett. 2010 Sep 1;20(17):5175-8. doi: 10.1016/j.bmcl.2010.07.007. Epub 2010 Jul 8.
9
mGluR4-positive allosteric modulation as potential treatment for Parkinson's disease.mGluR4 阳性变构调节作为治疗帕金森病的潜在方法。
Future Med Chem. 2009 Jun;1(3):501-13. doi: 10.4155/fmc.09.38.
10
Recent progress in the development of mGluR4 positive allosteric modulators for the treatment of Parkinson's disease.mGluR4 正变构调节剂治疗帕金森病研究进展
Curr Top Med Chem. 2009;9(10):949-63.
Zotero 插件