Quinolizidinone Carboxylic Acids as CNS Penetrant, Selective M1 Allosteric Muscarinic Receptor Modulators

被引：63

作者：

Kuduk, Scott D. ^{[1
]}

Chang, Ronald K. ^{[1
]}

Di Marco, Christina N. ^{[1
]}

Ray, William J. ^{[2
]}

Ma, Lei ^{[2
]}

Wittmann, Marion ^{[2
]}

Seager, Matthew A. ^{[2
]}

Koeplinger, Kenneth A. ^{[3
]}

Thompson, Charles D. ^{[3
]}

Hartman, George D. ^{[1
]}

Bilodeau, Mark T. ^{[1
]}

机构：

[1] Merck Res Labs, Dept Med Chem, West Point, PA 19486 USA

[2] Merck Res Labs, Dept Alzheimers Res, West Point, PA 19486 USA

[3] Merck Res Labs, Dept Drug Metab, West Point, PA 19486 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2010年 / 1卷 / 06期

关键词：

Quinolizidinone; M-1 muscarinic receptor; allosteric modulator; cognition; Alzheimer's;

D O I：

10.1021/ml100095k

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

Positive allosteric modulation of the M, muscarinic receptor represents an approach to treat the cognitive decline in patients with Alzheimer's disease. Replacement of a quinolone ring system in a quinolone carboxylic acid series of M, modulators with a quinolizidinone bearing a basic amine linkage led to a series of compounds with higher free fraction, enhanced CNS exposure, and improved efficacy in rodent in vivo models of cognition.

引用

页码：263 / 267

页数：5

共 18 条

[1]

Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease [J].

Bodick, NC ;

Offen, WW ;

Levey, AI ;

Cutler, NR ;

Gauthier, SG ;

Satlin, A ;

Shannon, HE ;

Tollefson, GD ;

Rasmussen, K ;

Bymaster, FP ;

Hurley, DJ ;

Potter, WZ ;

Paul, SM .

ARCHIVES OF NEUROLOGY, 1997, 54 (04) :465-473

[2]

BONNER TI, 1989, TRENDS PHARMACOL SCI, P11

[3]

THE MOLECULAR-BASIS OF MUSCARINIC RECEPTOR DIVERSITY [J].

BONNER, TI .

TRENDS IN NEUROSCIENCES, 1989, 12 (04) :148-151

[4]

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

[5]

Subtype-selective allosteric modulators of muscarinic receptors for the treatment of CNS disorders [J].

Conn, P. Jeffrey ;

Jones, Carrie K. ;

Lindsley, Craig W. .

TRENDS IN PHARMACOLOGICAL SCIENCES, 2009, 30 (03) :148-155

[6]

Abnormalities of neural circuitry in Alzheimer's disease - Hippocampus and cortical cholinergic innervation [J].

Geula, C .

NEUROLOGY, 1998, 51 (01) :S18-S29

[7]

Muscarinic agonists and antagonists in the treatment of Alzheimer's disease [J].

Greenlee, W ;

Clader, J ;

Asberom, T ;

McCombie, S ;

Ford, J ;

Guzik, H ;

Kozlowski, J ;

Li, S ;

Liu, C ;

Lowe, D ;

Vice, S ;

Zhao, H ;

Zhou, G ;

Billard, W ;

Binch, H ;

Crosby, R ;

Duffy, R ;

Lachowicz, J ;

Coffin, V ;

Watkins, R ;

Ruperto, V ;

Strader, C ;

Taylor, L ;

Cox, K .

FARMACO, 2001, 56 (04) :247-250

[8]

Novel Selective Allosteric Activator of the M1 Muscarinic Acetylcholine Receptor Regulates Amyloid Processing and Produces Antipsychotic-Like Activity in Rats [J].

Jones, Carrie K. ;

Brady, Ashley E. ;

Davis, Albert A. ;

Xiang, Zixiu ;

Bubser, Michael ;

Tantawy, Mohammed Noor ;

Kane, Alexander S. ;

Bridges, Thomas M. ;

Kennedy, J. Phillip ;

Bradley, Stefania R. ;

Peterson, Todd E. ;

Ansari, M. Sib ;

Baldwin, Ronald M. ;

Kessler, Robert M. ;

Deutch, Ariel Y. ;

Lah, James J. ;

Levey, Allan I. ;

Lindsley, Craig W. ;

Conn, P. Jeffrey .

JOURNAL OF NEUROSCIENCE, 2008, 28 (41) :10422-10433

[9]

Design and synthesis of highly sensitive and selective fluorescein-derived magnesium fluorescent probes and application to intracellular 3D Mg2+ imaging [J].

Komatsu, H ;

Iwasawa, N ;

Citterio, D ;

Suzuki, Y ;

Kubota, T ;

Tokuno, K ;

Kitamura, Y ;

Oka, K ;

Suzuki, K .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2004, 126 (50) :16353-16360

[10]

Kuduk S.D., 2009, BIOORG MED CHEM LETT, V19, P657

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