Discovery of 4-alkoxy-6-methylpicolinamide negative allosteric modulators of metabotropic glutamate receptor subtype 5

被引：5

作者：

Felts, Andrew S. ^{[1
,2
]}

Bollinger, Katrina A. ^{[1
,2
]}

Brassard, Christopher J. ^{[1
,2
]}

Rodriguez, Alice L. ^{[1
,2
]}

Morrison, Ryan D. ^{[1
,2
]}

Daniels, J. Scott ^{[1
,2
]}

Blobaum, Anna L. ^{[1
,2
]}

Niswender, Colleen M. ^{[1
,2
,5
]}

Jones, Carrie K. ^{[1
,2
,5
]}

Conn, P. Jeffrey ^{[1
,2
,5
]}

Emmitte, Kyle A. ^{[1
,2
,5
,6
]}

Lindsley, Craig W. ^{[1
,2
,3
,4
]}

机构：

[1] Vanderbilt Univ, Vanderbilt Ctr Neurosci Drug Discovery, Med Ctr, Nashville, TN 37232 USA

[2] Vanderbilt Univ, Dept Pharmacol, Sch Med, Nashville, TN 37232 USA

[3] Vanderbilt Univ, Dept Chem, Nashville, TN 37232 USA

[4] Vanderbilt Univ, Dept Biochem, Nashville, TN 37232 USA

[5] Vanderbilt Univ, Vanderbilt Kennedy Ctr, Sch Med, Nashville, TN 37232 USA

[6] Univ North Texas Hlth Sci Ctr, UNT Syst Coll Pharm, Dept Pharmaceut Sci, 3500 Camp Bowie Blvd, Ft Worth, TX 76107 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2019年 / 29卷 / 01期

关键词：

mGlu(5); Metabotropic glutamate receptor; Negative allosteric modulator (NAM); CNS; Structure-Activity Relationship (SAR); BASIMGLURANT; ANTAGONISTS; MGLU(5); POTENT; IDENTIFICATION; REINFORCEMENT; REINSTATEMENT; PHARMACOLOGY; MAVOGLURANT; VU0424238;

D O I：

10.1016/j.bmcl.2018.11.017

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

This letter describes the further chemical optimization of VU0424238 (auglurant), an mGlu(5) NAM clinical candidate that failed in non-human primate (NHP) 28 day toxicology due to accumulation of a species-specific aldehyde oxidase (AO) metabolite of the pyrimidine head group. Here, we excised the pyrimidine moiety, identified the minimum pharmacophore, and then developed a new series of saturated ether head groups that ablated any AO contribution to metabolism. Putative back-up compounds in this novel series provided increased sp(3) character, uniform CYP450-mediated metabolism across species, good functional potency and high CNS penetration. Key to the optimization was a combination of matrix and iterative libraries that allowed rapid surveillance of multiple domains of the allosteric ligand.

引用

页码：47 / 50

页数：4

共 50 条

[21] Identification of Novel Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5 Acting at Site Distinct from 2-Methyl-6-(phenylethynyl)-pyridine Binding
Butkiewicz, Mariusz
Rodriguez, Alice L.
Rainey, Shane E.
Wieling, Joshua
Luscombe, Vincent B.
Stauffer, Shaun R.
Lindsley, Craig W.
Conn, P. Jeffrey
Meiler, Jens
ACS CHEMICAL NEUROSCIENCE, 2019, 10 (08): : 3427 - 3436
[22] Progress in the Developement of Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 2
Trabanco, A. A.
Cid, J. M.
Lavreysen, H.
Macdonald, G. J.
Tresadern, G.
CURRENT MEDICINAL CHEMISTRY, 2011, 18 (01) : 47 - 68
[23] A novel series of metabotropic glutamate receptor 5 negative allosteric modulators based on a 4,5,6,7-tetrahydropyrazolo [1,5-a]pyridine core
Duvey, Guillaume
Perry, Benjamin
Le Poul, Emmanuel
Poli, Sonia
Bonnet, Beatrice
Lambeng, Nathalie
Charvin, Delphine
Donovan-Rodrigues, Tansy
Haddouk, Hasnaa
Gagliardi, Stefania
Rocher, Jean-Philippe
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2013, 23 (16) : 4523 - 4527
[24] Discovery of a Selective and CNS Penetrant Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 3 with Antidepressant and Anxiolytic Activity in Rodents
Engers, Julie L.
Rodriguez, Alice L.
Konkol, Leah C.
Morrison, Ryan D.
Thompson, Analisa D.
Byers, Frank W.
Blobaum, Anna L.
Chang, Sichen
Venable, Daryl F.
Loch, Matthew T.
Niswender, Colleen M.
Daniels, J. Scott
Jones, Carrie K.
Conn, P. Jeffrey
Lindsley, Craig W.
Emmitte, Kyle A.
JOURNAL OF MEDICINAL CHEMISTRY, 2015, 58 (18) : 7485 - 7500
[25] Identification of Allosteric Modulators of Metabotropic Glutamate 7 Receptor Using Proteochemometric Modeling
Tresadern, Gary
Trabanco, Andres A.
Perez-Benito, Laura
Overington, John P.
van Vlijmen, Herman W. T.
van Westen, Gerard J. P.
JOURNAL OF CHEMICAL INFORMATION AND MODELING, 2017, 57 (12) : 2976 - 2985
[26] Pharmacological and molecular characterization of the positive allosteric modulators of metabotropic glutamate receptor 2
Lundstrom, L.
Bissantz, C.
Beck, J.
Dellenbach, M.
Woltering, T. J.
Wichmann, J.
Gatti, S.
NEUROPHARMACOLOGY, 2016, 111 : 253 - 265
[27] Iterative experimental and virtual high-throughput screening identifies metabotropic glutamate receptor subtype 4 positive allosteric modulators
Mueller, Ralf
Dawson, Eric S.
Niswender, Colleen M.
Butkiewicz, Mariusz
Hopkins, Corey R.
Weaver, C. David
Lindsley, Craig W.
Conn, P. Jeffrey
Meiler, Jens
JOURNAL OF MOLECULAR MODELING, 2012, 18 (09) : 4437 - 4446
[28] Exploring the Binding Mechanism of Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators in Clinical Trials by Molecular Dynamics Simulations
Fu, Tingting
Zheng, Guoxun
Tu, Gao
Yang, Fengyuan
Chen, Yuzong
Yao, Xiaojun
Li, Xiaofeng
Xue, Weiwei
Zhu, Feng
ACS CHEMICAL NEUROSCIENCE, 2018, 9 (06): : 1492 - 1502
[29] In vitro binding of a radio-labeled positive allosteric modulator for metabotropic glutamate receptor subtype 5
Zysk, John R.
Spear, Nathan
Fieles, William
Stein, Mark M.
Sygowski, Linda S.
King, Megan M.
Hoesch, Valerie
Hastings, Richard
Brockel, Becky
Do, Mylinh
Strom, Peter
Gadient, Reto
Chhajlani, Vijay
Elmore, Charles S.
Maier, Donna L.
SYNAPSE, 2013, 67 (03) : 135 - 144
[30] Novel substituted 4-(Arylethynyl)-Pyrrolo[2,3-d]pyrimidines negative allosteric modulators (NAMs) of the metabotropic glutamate receptor subtype 5 (mGlu5) Treat depressive disorder in mice
Du, Yonglei
Gao, Feng
Sun, Hongwei
Wu, Chenglin
Zhu, Guoqi
Zhu, Manzhou
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2023, 261

← 1 2 3 4 5 →