The Synthesis and Biological Evaluation of Quinolyl-piperazinyl Piperidines as Potent Serotonin 5-HT1A Antagonists

被引：13

作者：

Childers, Wayne E., Jr. ^{[1
]}

Havran, Lisa M. ^{[1
]}

Asselin, Magda ^{[1
]}

Bicksler, James J. ^{[1
]}

Chong, Dan C. ^{[1
]}

Grosu, George T. ^{[1
]}

Shen, Zhongqi ^{[1
]}

Abou-Gharbia, Magid A. ^{[1
]}

Bach, Alvin C., III ^{[1
]}

Harrison, Boyd L. ^{[1
]}

Kagan, Natasha ^{[1
]}

Kleintop, Teresa ^{[1
]}

Magolda, Ronald ^{[1
]}

Marathias, Vasilios ^{[1
]}

Robichaud, Albert J. ^{[1
]}

Sabb, Annmarie L. ^{[1
]}

Zhang, Mei-Yi ^{[1
]}

Andree, Terrance H. ^{[2
]}

Aschmies, Susan H. ^{[2
]}

Beyer, Chad ^{[2
]}

Comery, Thomas A. ^{[2
]}

Day, Mark ^{[2
]}

Grauer, Steven M. ^{[2
]}

Hughes, Zoe A. ^{[2
]}

Rosenzweig-Lipson, Sharon ^{[2
]}

Platt, Brian ^{[2
]}

Pulicicchio, Claudine ^{[2
]}

Smith, Deborah E. ^{[2
]}

Sukoff-Rizzo, Stacy J. ^{[2
]}

Sullivan, Kelly M. ^{[2
]}

Adedoyin, Adedayo ^{[3
]}

Huselton, Christine ^{[3
]}

Hirst, Warren D. ^{[2
]}

机构：

[1] Pfizer Global Res & Dev, Chem Sci, Princeton, NJ 08543 USA

[2] Pfizer Global Res & Dev, Neurosci, Princeton, NJ 08543 USA

[3] Pfizer Global Res & Dev, Drug Safety & Metab, Princeton, NJ 08543 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 10期

关键词：

SCHEDULE-INDUCED-POLYDIPSIA; RECEPTOR ANTAGONISTS; ALZHEIMERS-DISEASE; SEXUAL DYSFUNCTION; IN-VIVO; REUPTAKE INHIBITORS; TRANSGENIC MICE; FRONTAL-CORTEX; MOUSE MODEL; RAT-BRAIN;

D O I：

10.1021/jm1000908

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

As part of an effort to identify 5-HT1A antagonists that did not possess typical arylalkylamine or keto/amido-alkyl aryl piperazine scaffolds, prototype compound 10a was identified from earlier work in a combined 5-HT1A antagonist/SSRI program. This quinolyl-piperazinyl piperidine analogue displayed potent, selective 5-HT1A antagonism but suffered from poor oxidative metabolic stability, resulting in low exposure following oral administration. SA R studies, driven primarily by in vitro liver microsomal stability assessment, identified compound lob, which displayed improved oral bioavailability and lower intrinsic clearance. Further changes to the scaffold (e.g., 10r) resulted in a loss in potency. Compound 10b displayed cognitive enhancing effects in a number of animal models of learning and memory, enhanced the antidepressant-like effects of the SSRI fluoxetine, and reversed the sexual dysfunction induced by chronic fluoxetine treatment.

引用

页码：4066 / 4084

页数：19

共 52 条

[41] The serotonin1A receptor partial agonist S15535 [4-(benzodioxan-5-yl)1-(indan-2-yl)piperazine] enhances cholinergic transmission and cognitive function in rodents:: A combined neurochemical and behavioral analysis
Millan, MJ
Gobert, A
Roux, S
Porsolt, R
Meneses, A
Carli, M
Di Cara, B
Jaffard, R
Rivet, JM
Lestage, P
Mocaer, E
Peglion, JL
Dekeyne, A
[J]. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2004, 311 (01) : 190 - 203
[42] Norden M.J., 1994, Depression and Anxiety, V2, P109, DOI [DOI 10.1002/depr.3050020208, DOI 10.1002/DEPR.3050020208]
[43] The role of 5-HT1A receptors in learning and memory
Ogren, Sven Ove
Eriksson, Therese M.
Elvander-Tottie, Elin
D'Addario, Claudio
Ekstrom, Joanna C.
Svenningsson, Per
Meister, Bjorn
Kehr, Jan
Stiedl, Oliver
[J]. BEHAVIOURAL BRAIN RESEARCH, 2008, 195 (01) : 54 - 77
[44] DISCRIMINATION OF MULTIPLE [H-3]5-HYDROXYTRYPTAMINE BINDING-SITES BY THE NEUROLEPTIC SPIPERONE IN RAT-BRAIN
PEDIGO, NW
YAMAMURA, HI
NELSON, DL
[J]. JOURNAL OF NEUROCHEMISTRY, 1981, 36 (01) : 220 - 226
[45] A novel approach for predicting antidepressant-induced sexual dysfunction in rats
Rizzo, Stacey J. Sukoff
Schechter, Lee E.
Rosenzweig-Lipson, Sharon
[J]. PSYCHOPHARMACOLOGY, 2008, 195 (04) : 459 - 467
[46] Antidepressant-like effects of the novel, selective, 5-HT2C receptor agonist WAY-163909 in rodents
Rosenzweig-Lipson, Sharon
Sabb, Annmarie
Stack, Gary
Mitchell, Paul
Lucki, Irwin
Malberg, Jessica E.
Grauer, Steve
Brennan, Julie
Cryan, John F.
Rizzo, Stacey J. Sukoff
Dunlop, John
Barrett, James E.
Marquis, Karen L.
[J]. PSYCHOPHARMACOLOGY, 2007, 192 (02) : 159 - 170
[47] Lecozotan (SRA-333): A selective serotonin 1A receptor antagonist that enhances the stimulated release of glutamate and acetylcholine in the hippocampus and possesses cognitive-enhancing properties
Schechter, LE
Smith, DL
Rosenzweig-Lipson, S
Sukoff, SJ
Dawson, LA
Marquis, K
Jones, D
Piesla, M
Andree, T
Nawoschik, S
Harder, JA
Womack, MD
Buccafusco, J
Terry, AV
Hoebel, B
Rada, P
Kelly, M
Abou-Gharbia, M
Barrett, JE
Childers, W
[J]. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2005, 314 (03) : 1274 - 1289
[48] Slcraup Z. H, 1880, CHEM BER, V13, P2086
[49] SUKOFFRIZZO SJ, 2009, J NEUROPSYCHOPHARMAC, V12, P1045
[50] WEN H, 2008, Patent No. 2008101139

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