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

[1] Synthesis and SAR of adatanserin:: Novel adamantyl aryl- and heteroarylpiperazines with dual serotonin 5-HT1A and 5-HT2 activity as potential anxiolytic and antidepressant agents
Abou-Gharbia, MA
Childers, WE
Fletcher, H
McGaughey, G
Patel, U
Webb, MB
Yardley, J
Andree, T
Boast, C
Kucharik, RJ
Marquis, K
Morris, H
Scerni, R
Moyer, JA
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (25) : 5077 - 5094
[2] ASSELIN M, 2009, 41 NAT ORG CHEM S BO, pB11
[3] ASSELIN M, 2006, Patent No. 7671056
[4] Effects of 5-HT1A receptor antagonists on hippocampal 5-hydroxytryptamine levels: (S)-WAY100135, but not WAY100635, has partial agonist properties
Assie, MB
Koek, W
[J]. EUROPEAN JOURNAL OF PHARMACOLOGY, 1996, 304 (1-3) : 15 - 21
[5] Selective serotonin re-uptake inhibitor treatment-emergent sexual dysfunction: randomized double-blind placebo-controlled parallel-group fixed-dose study of a potential adjuvant compound, VML-670
Baldwin, David
Hutchison, John
Donaldson, Kirsteen
Shaw, Bob
Smithers, Andrew
[J]. JOURNAL OF PSYCHOPHARMACOLOGY, 2008, 22 (01) : 55 - 63
[6] Blier P, 1998, J CLIN PSYCHIAT, V59, P16
[7] BLIER P, 1987, J CLIN PSYCHOPHARM, V7, pS24
[8] NEUROTRANSMISSION - THE LINK INTEGRATING ALZHEIMER RESEARCH
BOWEN, DM
FRANCIS, PT
CHESSELL, IP
WEBSTER, MT
[J]. TRENDS IN NEUROSCIENCES, 1994, 17 (04) : 149 - 150
[9] Recent developments in the design of anti-depressive therapies: Targeting the serotonin transporter
Butler, S. G.
Meegan, M. J.
[J]. CURRENT MEDICINAL CHEMISTRY, 2008, 15 (17) : 1737 - 1761
[10] COMPARATIVE ANATOMICAL DISTRIBUTION OF 5-HT1A RECEPTOR MESSENGER-RNA AND 5-HT1A BINDING IN RAT-BRAIN - A COMBINED INSITU HYBRIDIZATION INVITRO RECEPTOR AUTORADIOGRAPHIC STUDY
CHALMERS, DT
WATSON, SJ
[J]. BRAIN RESEARCH, 1991, 561 (01) : 51 - 60

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