Discovery of (R)-(2-Fluoro-4-((-4-methoxyphenyl)ethynyl)phenyl) (3-Hydroxypiperidin-1-yl)methanone (ML337), An mGlu3 Selective and CNS Penetrant Negative Allosteric Modulator (NAM)

被引：56

作者：

Wenthur, Cody J. ^{[1
,2
,3
]}

Morrison, Ryan ^{[1
,2
,3
]}

Felts, Andrew S. ^{[1
,2
,3
]}

Smith, Katrina A. ^{[1
,2
,3
]}

Engers, Julie L. ^{[1
,2
,3
]}

Byers, Frank W. ^{[1
,2
,3
]}

Daniels, J. Scott ^{[1
,2
,3
]}

Emmitte, Kyle A. ^{[1
,2
,3
,4
]}

Conn, P. Jeffrey ^{[1
,2
,3
]}

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

机构：

[1] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA

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

[3] Vanderbilt Univ, Med Ctr, Vanderbilt Specialized Chem Accelerated Probe Dev, Nashville, TN 37232 USA

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

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 12期

关键词：

METABOTROPIC GLUTAMATE RECEPTORS; PHARMACOLOGICAL CHARACTERIZATION; RECENT PROGRESS; IDENTIFICATION;

D O I：

10.1021/jm400439t

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A multidimensional, iterative parallel synthesis effort identified a series of highly selective mGlu(3) NAMs with submicromolar potency and good CNS penetration. Of these, ML337 resulted (mGlu(3) IC50 = 593 nM, mGlu(2) IC50 >30 mu M) with B:P ratios of 0.92 (mouse) to 0.3 (rat). DMPK profiling and shallow SAR led to the incorporation of deuterium atoms to address a metabolic soft spot, which subsequently lowered both in vitro and in vivo clearance by >50%.

引用

收藏

页码：5208 / 5212

页数：5

相关论文

共 16 条

[1] Characterization of an mGluR2/3 Negative Allosteric Modulator in Rodent Models of Depression [J].

Campo, Brice ;

Kalinichev, Mikhail ;

Lambeng, Nathalie ;

El Yacoubi, M. ;

Royer-Urios, Isabelle ;

Schneider, Manfred ;

Legrand, Coline ;

Parron, Delphine ;

Girard, Francoise ;

Bessif, Abdelhak ;

Poli, Sonia ;

Vaugeois, Jean-Marie ;

Le Poul, Emmanuel ;

Celanire, Sylvain .

JOURNAL OF NEUROGENETICS, 2011, 25 (04) :152-166

[2] Targeting Group II Metabotropic Glutamate (mGlu) Receptors for the Treatment of Psychosis Associated with Alzheimer's Disease: Selective Activation of mGlu2 Receptors Amplifies β-Amyloid Toxicity in Cultured Neurons, Whereas Dual Activation of mGlu2 and mGlu3 Receptors Is Neuroprotective [J].

Caraci, Filippo ;

Molinaro, Gemma ;

Battaglia, Giuseppe ;

Giuffrida, Maria Laura ;

Riozzi, Barbara ;

Traficante, Anna ;

Bruno, Valeria ;

Cannella, Milena ;

Merlo, Sara ;

Wang, Xushan ;

Heinz, Beverly A. ;

Nisenbaum, Eric S. ;

Britton, Thomas C. ;

Drago, Filippo ;

Sortino, Maria Angela ;

Copani, Agata ;

Nicoletti, Ferdinando .

MOLECULAR PHARMACOLOGY, 2011, 79 (03) :618-626

[3] Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders [J].

Conn, P. Jeffrey ;

Christopoulos, Arthur ;

Lindsley, Craig W. .

NATURE REVIEWS DRUG DISCOVERY, 2009, 8 (01) :41-54

[4] Activation of metabotropic glutamate receptors as a novel approach for the treatment of schizophrenia [J].

Conn, P. Jeffrey ;

Lindsley, Craig W. ;

Jones, Carrie K. .

TRENDS IN PHARMACOLOGICAL SCIENCES, 2009, 30 (01) :25-31

[5] Pharmacology and functions of metabotropic glutamate receptors [J].

Conn, PJ ;

Pin, JP .

ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, 1997, 37 :205-237

[6] Recent Advances in the Design and Development of Novel Negative Allosteric Modulators of mGlu5 [J].

Emmitte, Kyle A. .

ACS CHEMICAL NEUROSCIENCE, 2011, 2 (08) :411-432

[7] The group II metabotropic glutamate receptor 3 (mGluR3, mGlu3, GRM3): expression, function and involvement in schizophrenia [J].

Harrison, P. J. ;

Lyon, L. ;

Sartorius, L. J. ;

Burnet, P. W. J. ;

Lane, T. A. .

JOURNAL OF PSYCHOPHARMACOLOGY, 2008, 22 (03) :308-322

[8] Allosteric Modulation of Seven Transmembrane Spanning Receptors: Theory, Practice, and Opportunities for Central Nervous System Drug Discovery [J].

Melancon, Bruce J. ;

Hopkins, Corey R. ;

Wood, Michael R. ;

Emmitte, Kyle A. ;

Niswender, Colleen M. ;

Christopoulos, Arthur ;

Conn, P. Jeffrey ;

Lindsley, Craig W. .

JOURNAL OF MEDICINAL CHEMISTRY, 2012, 55 (04) :1445-1464

[9] Synthesis, pharmacological characterization, and molecular modeling of heterobicyclic amino acids related to (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740): Identification of two new potent, selective, and systemically active agonists for group II metabotropic glutamate receptors [J].

Monn, JA ;

Valli, MJ ;

Massey, SM ;

Hansen, MM ;

Kress, TJ ;

Wepsiec, JP ;

Harkness, AR ;

Grutsch, JL ;

Wright, RA ;

Johnson, BG ;

Andis, SL ;

Kingston, A ;

Tomlinson, R ;

Lewis, R ;

Griffey, KR ;

Tizzano, JP ;

Schoepp, DD .

JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (06) :1027-1040

[10] The use of deuterium isotope effects to probe the active site properties, mechanism of cytochrome P450-catalyzed reactions, and mechanisms of metabolically dependent toxicity [J].

Nelson, SD ;

Trager, WF .

DRUG METABOLISM AND DISPOSITION, 2003, 31 (12) :1481-1498