SAR and biological evaluation of SEN12333/WAY-317538: Novel alpha 7 nicotinic acetylcholine receptor agonist

被引：36

作者：

Haydar, Simon N. ^{[1
]}

Ghiron, Chiara ^{[2
]}

Bettinetti, Laura ^{[2
]}

Bothmann, Hendrick ^{[2
]}

Comery, Thomas A. ^{[1
]}

Dunlop, John ^{[1
]}

La Rosa, Salvatore ^{[2
]}

Micco, Iolanda ^{[2
]}

Pollastrini, Martina ^{[2
]}

Quinn, Joanna ^{[2
]}

Roncarati, Renza ^{[2
]}

Scali, Carla ^{[2
]}

Valacchi, Michela ^{[2
]}

Varrone, Maurizio ^{[2
]}

Zanaletti, Riccardo ^{[2
]}

机构：

[1] Wyeth Ayerst Res, Chem Sci & Neurosci Discovery Res, Princeton, NJ 08543 USA

[2] Siena Biotech SpA, I-53100 Siena, Italy

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2009年 / 17卷 / 14期

关键词：

Neuronal nicotinic acetylcholine receptors; Nicotinic ligands; Cognition; Auditory sensory gating; IN-VITRO; VIVO;

D O I：

10.1016/j.bmc.2009.05.040

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Alpha 7 nicotinic acetylcholine receptor (alpha(7) nAChR) agonists are promising therapeutic candidates for the treatment of cognitive impairment associated with a variety of disorders including Alzheimer's disease and schizophrenia. Alpha 7 nAChRs are expressed in brain regions associated with cognitive function, regulate cholinergic neurotransmission and have been shown to be down regulated in both schizophrenia and Alzheimer's disease. Herein we report a novel, potent small molecule agonist of the alpha 7 nAChR, SEN12333/WAY-317538. This compound is a selective agonist of the alpha(7) nAChR with excellent in vitro and in vivo profiles, excellent brain penetration and oral bioavailability, and demonstrates in vivo efficacy in multiple behavioural cognition models. The SAR and biological evaluation of this series of compounds are discussed. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：5247 / 5258

页数：12

共 15 条

[1] Discovery of N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide as an agonist of the α7 nicotinic acetylcholine receptor:: In vitro and in vivo activity [J].

Acker, Brad A. ;

Jacobsen, E. Jon ;

Rogers, Bruce N. ;

Wishka, Donn G. ;

Reitz, Steven C. ;

Piotrowski, David W. ;

Myers, Jason K. ;

Wolfe, Mark L. ;

Groppi, Vincent E. ;

Thornburgh, Bruce A. ;

Tinholt, Paula M. ;

Walters, Rodney R. ;

Olson, Barbara A. ;

Fitzgerald, Laura ;

Staton, Brian A. ;

Raub, Thomas J. ;

Krause, Michael ;

Li, Kai S. ;

Hoffmann, William E. ;

Hajos, Mihaly ;

Hurst, Raymond S. ;

Walker, Daniel P. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2008, 18 (12) :3611-3615

[2] In vitro screening strategies for nicotinic receptor ligands [J].

Dunlop, John ;

Roncarati, Renza ;

Jow, Brian ;

Bothmann, Hendrick ;

Lock, Tim ;

Kowal, Dianne ;

Bowlby, Mark ;

Terstappen, Georg C. .

BIOCHEMICAL PHARMACOLOGY, 2007, 74 (08) :1172-1181

[3] The α7-nicotinic acetylcholine receptor and the pathology of hippocampal interneurons in schizophrenia [J].

Freedman, R ;

Adams, CE ;

Leonard, S .

JOURNAL OF CHEMICAL NEUROANATOMY, 2000, 20 (3-4) :299-306

[4]

GAVIRAGHI G, 2006, Patent No. 2006008133

[5] Brain neuronal nicotinic receptors as new targets for drug discovery [J].

Gotti, C ;

Riganti, L ;

Vailanti, S ;

Clementi, F .

CURRENT PHARMACEUTICAL DESIGN, 2006, 12 (04) :407-428

[6] The brain α7 nicotinic receptor may be an important therapeutic target for the treatment of Alzheimer's disease:: studies with DMXBA (GTS-21) [J].

Kem, WR .

BEHAVIOURAL BRAIN RESEARCH, 2000, 113 (1-2) :169-181

[7] Ligand-free palladium catalysis of the Suzuki reaction in water using microwave heating [J].

Leadbeater, NE ;

Marco, M .

ORGANIC LETTERS, 2002, 4 (17) :2973-2976

[8]

Lindstrom J, 1996, Ion Channels, V4, P377

[9]

LIPPIELLO PM, 2004, CURR TOP MED CHEM, V4, P267

[10] Nicotine and nicotinic receptor involvement in neuropsychiatric disorders [J].

Newhouse, P ;

Singh, A ;

Potter, A .

CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2004, 4 (03) :267-282

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