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。
Synthesis and SAR of novel, 4-(phenylsulfamoyl)phenylacetamide mGlu4 positive allosteric modulators (PAMs) identified by functional high-throughput screening (HTS).
机构信息
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
出版信息
Bioorg Med Chem Lett. 2010 Sep 1;20(17):5175-8. doi: 10.1016/j.bmcl.2010.07.007. Epub 2010 Jul 8.
Abstract
Herein we disclose the synthesis and SAR of a series of 4-(phenylsulfamoyl)phenylacetamide compounds as mGlu(4) positive allosteric modulators (PAMs) that were identified via a functional HTS. An iterative parallel approach to these compounds culminated in the discovery of VU0364439 (11) which represents the most potent (19.8 nM) mGlu(4) PAM reported to date.
摘要
在此，我们披露了一系列 4-(苯磺酰胺基)苯乙酰胺化合物的合成和 SAR 研究，这些化合物是通过功能性 HTs 鉴定为 mGlu(4) 正变构调节剂 (PAMs)。对这些化合物的迭代平行方法最终发现了 VU0364439（11），它是迄今为止报道的最有效的 mGlu(4) PAM（19.8 nM）。
相似文献
1
Synthesis and SAR of novel, 4-(phenylsulfamoyl)phenylacetamide mGlu4 positive allosteric modulators (PAMs) identified by functional high-throughput screening (HTS).
Bioorg Med Chem Lett. 2010 Sep 1;20(17):5175-8. doi: 10.1016/j.bmcl.2010.07.007. Epub 2010 Jul 8.
2
Discovery and SAR of a novel series of non-MPEP site mGlu₅ PAMs based on an aryl glycine sulfonamide scaffold.
Bioorg Med Chem Lett. 2012 Dec 15;22(24):7388-92. doi: 10.1016/j.bmcl.2012.10.068. Epub 2012 Oct 23.
3
Discovery and characterization of a novel series of N-phenylsulfonyl-1H-pyrrole picolinamides as positive allosteric modulators of the metabotropic glutamate receptor 4 (mGlu4).
Bioorg Med Chem Lett. 2016 Jul 1;26(13):2984-2987. doi: 10.1016/j.bmcl.2016.05.029. Epub 2016 May 11.
4
Discovery of dual positive allosteric modulators (PAMs) of the metabotropic glutamate 2 receptor and CysLT1 antagonists for treating migraine headache.
Bioorg Med Chem Lett. 2017 Jan 15;27(2):323-328. doi: 10.1016/j.bmcl.2016.11.049. Epub 2016 Nov 18.
5
Solution-phase parallel synthesis and SAR of homopiperazinyl analogs as positive allosteric modulators of mGlu₄.
ACS Comb Sci. 2011 Mar 14;13(2):159-65. doi: 10.1021/co1000508. Epub 2011 Feb 21.
6
Discovery of 1,5-disubstituted pyridones: a new class of positive allosteric modulators of the metabotropic glutamate 2 receptor.
ACS Chem Neurosci. 2010 Dec 15;1(12):788-95. doi: 10.1021/cn1000638. Epub 2010 Aug 23.
7
Pyrimidine methyl anilines: selective potentiators for the metabotropic glutamate 2 receptor.
Bioorg Med Chem Lett. 2004 Oct 18;14(20):5071-4. doi: 10.1016/j.bmcl.2004.07.079.
8
Pharmacological and molecular characterization of the positive allosteric modulators of metabotropic glutamate receptor 2.
Neuropharmacology. 2016 Dec;111:253-265. doi: 10.1016/j.neuropharm.2016.08.032. Epub 2016 Aug 30.
9
Lead optimization of the VU0486321 series of mGlu PAMs. Part 4: SAR reveals positive cooperativity across multiple mGlu receptor subtypes leading to subtype unselective PAMs.
Bioorg Med Chem Lett. 2021 Jan 15;32:127724. doi: 10.1016/j.bmcl.2020.127724. Epub 2020 Nov 27.
10
4-(1-Phenyl-1H-pyrazol-4-yl)quinolines as novel, selective and brain penetrant metabotropic glutamate receptor 4 positive allosteric modulators.
Bioorg Med Chem Lett. 2012 May 1;22(9):3235-9. doi: 10.1016/j.bmcl.2012.03.032. Epub 2012 Mar 15.
引用本文的文献
1
New 1,2,4-oxadiazole derivatives with positive mGlu receptor modulation activity and antipsychotic-like properties.
J Enzyme Inhib Med Chem. 2022 Dec;37(1):211-225. doi: 10.1080/14756366.2021.1998022.
2
Recent advances in the medicinal chemistry of group II and group III mGlu receptors.
Medchemcomm. 2017 Jan 13;8(3):501-515. doi: 10.1039/c6md00612d. eCollection 2017 Mar 1.
3
Discovery and characterization of a novel series of N-phenylsulfonyl-1H-pyrrole picolinamides as positive allosteric modulators of the metabotropic glutamate receptor 4 (mGlu4).
Bioorg Med Chem Lett. 2016 Jul 1;26(13):2984-2987. doi: 10.1016/j.bmcl.2016.05.029. Epub 2016 May 11.
4
Discovery of 3-aminopicolinamides as metabotropic glutamate receptor subtype 4 (mGlu4) positive allosteric modulator warheads engendering CNS exposure and in vivo efficacy.
Bioorg Med Chem Lett. 2016 Jun 15;26(12):2915-2919. doi: 10.1016/j.bmcl.2016.04.041. Epub 2016 Apr 19.
5
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).
ACS Chem Neurosci. 2016 Sep 21;7(9):1192-200. doi: 10.1021/acschemneuro.6b00035. Epub 2016 May 3.
6
Recent progress on the identification of metabotropic glutamate 4 receptor ligands and their potential utility as CNS therapeutics.
ACS Chem Neurosci. 2011 Aug 17;2(8):433-49. doi: 10.1021/cn200043e. Epub 2011 Jun 14.
7
Metabotropic glutamate receptor 4 in the basal ganglia of parkinsonian monkeys: ultrastructural localization and electrophysiological effects of activation in the striatopallidal complex.
Neuropharmacology. 2013 Mar;66:242-52. doi: 10.1016/j.neuropharm.2012.05.017. Epub 2012 May 23.
8
Iterative experimental and virtual high-throughput screening identifies metabotropic glutamate receptor subtype 4 positive allosteric modulators.
J Mol Model. 2012 Sep;18(9):4437-46. doi: 10.1007/s00894-012-1441-0. Epub 2012 May 17.
9
Functional selectivity induced by mGlu₄ receptor positive allosteric modulation and concomitant activation of Gq coupled receptors.
Neuropharmacology. 2013 Mar;66:122-32. doi: 10.1016/j.neuropharm.2012.03.003. Epub 2012 Mar 9.
10
Allosteric modulation of the group III mGlu4 receptor provides functional neuroprotection in the 6-hydroxydopamine rat model of Parkinson's disease.
Br J Pharmacol. 2012 Aug;166(8):2317-30. doi: 10.1111/j.1476-5381.2012.01943.x.
本文引用的文献
1
Role of GRM4 in idiopathic generalized epilepsies analysed by genetic association and sequence analysis.
Epilepsy Res. 2010 May;89(2-3):319-26. doi: 10.1016/j.eplepsyres.2010.02.004. Epub 2010 Mar 24.
2
mGluR4-positive allosteric modulation as potential treatment for Parkinson's disease.
Future Med Chem. 2009 Jun;1(3):501-13. doi: 10.4155/fmc.09.38.
3
Metabotropic glutamate receptors: physiology, pharmacology, and disease.
Annu Rev Pharmacol Toxicol. 2010;50:295-322. doi: 10.1146/annurev.pharmtox.011008.145533.
4
Recent progress in the development of mGluR4 positive allosteric modulators for the treatment of Parkinson's disease.
Curr Top Med Chem. 2009;9(10):949-63.
5
Synthesis and SAR of a novel positive allosteric modulator (PAM) of the metabotropic glutamate receptor 4 (mGluR4).
Bioorg Med Chem Lett. 2009 Sep 1;19(17):4967-70. doi: 10.1016/j.bmcl.2009.07.072. Epub 2009 Jul 18.
6
Synthesis and evaluation of a series of heterobiarylamides that are centrally penetrant metabotropic glutamate receptor 4 (mGluR4) positive allosteric modulators (PAMs).
J Med Chem. 2009 Jul 23;52(14):4115-8. doi: 10.1021/jm9005065.
7
Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4). Part II: Challenges in hit-to-lead.
Bioorg Med Chem Lett. 2009 Feb 1;19(3):962-6. doi: 10.1016/j.bmcl.2008.11.104. Epub 2008 Dec 25.
8
Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4): Part I. Discovery of pyrazolo[3,4-d]pyrimidines as novel mGluR4 positive allosteric modulators.
Bioorg Med Chem Lett. 2008 Oct 15;18(20):5626-30. doi: 10.1016/j.bmcl.2008.08.087. Epub 2008 Aug 29.
9
Discovery, characterization, and antiparkinsonian effect of novel positive allosteric modulators of metabotropic glutamate receptor 4.
Mol Pharmacol. 2008 Nov;74(5):1345-58. doi: 10.1124/mol.108.049551. Epub 2008 Jul 29.
10
Positive allosteric modulation of metabotropic glutamate 4 (mGlu4) receptors enhances spontaneous and evoked absence seizures.
Neuropharmacology. 2008 Feb;54(2):344-54. doi: 10.1016/j.neuropharm.2007.10.004. Epub 2007 Oct 16.
Zotero 插件