Synthesis and biological evaluation of novel N1-phenylsulphonyl indole derivatives as potent and selective 5-HT6R ligands for the treatment of cognitive disorders

被引：2

作者：

Nirogi, Ramakrishna V. S. ^{[1
]}

Bandyala, Thrinath Reddy ^{[1
,2
]}

Gangadasari, Pamuletinarasimha Reddy ^{[1
]}

Khagga, Mukkanti ^{[2
]}

机构：

[1] Suven Life Sci Ltd, Discovery Res, Rd 5,Ave 7, Hyderabad 500034, Andhra Pradesh, India

[2] Jawaharlal Nehru Technol Univ Hyderabad, Inst Sci & Technol, Ctr Chem Sci & Technol, Hyderabad, Andhra Pradesh, India

来源：

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY | 2016年 / 31卷

关键词：

5-Hydroxytryptamine-6; receptor; animal models; central nervous system; cognition; novel object recognition test; structure-activity relationship; PHARMACOLOGICAL EVALUATION; RECEPTOR ANTAGONISTS; SEROTONIN; BINDING; RAT; SB-271046; SYMPTOMS; CORTEX;

D O I：

10.3109/14756366.2015.1103233

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：

A series of 1-[3-(4-methyl piperazin-1-ylmethyl) phenylsulfonyl]-1H-indole and 1-[3-(4-ethyl piperazin-1-ylmethyl) phenylsulfonyl]-1H-indole derivatives were designed and synthesized as 5-HT6 receptor (5-HT6R) ligands. The lead compound 1-[4-methyl-3-(4-methyl piperazin-1-yl methyl) phenylsulfonyl]-1H-indole dihydrochloride (6b), in this series, has shown potent in vitro binding affinity, selectivity, good pharmacokinetics (PK) profile and activity in the animal models of cognition.

引用

页码：1 / 15

页数：15

共 47 条

[1] Lu AE58054, a 5-HT6 antagonist, reverses cognitive impairment induced by subchronic phencyclidine in a novel object recognition test in rats [J].

Arnt, Jorn ;

Bang-Andersen, Benny ;

Grayson, Ben ;

Bymaster, Franklin P. ;

Cohen, Michael P. ;

DeLapp, Neil W. ;

Giethlen, Bruno ;

Kreilgaard, Mads ;

McKinzie, David L. ;

Neill, Joanna C. ;

Nelson, David L. ;

Nielsen, Soren M. ;

Poulsen, Mette N. ;

Schaus, John M. ;

Witten, Louise M. .

INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY, 2010, 13 (08) :1021-1033

[2]

Beard CC, 2003, US Patent, Patent No. [0073700 A1, 0073700]

[3] Serotonin 5-HT6 Receptor Antagonists for the Treatment of Cognitive Deficiency in Alzheimer's Disease [J].

Benhamu, Bellinda ;

Martin-Fontecha, Mar ;

Vazquez-Villa, Henar ;

Pardo, Leonardo ;

Lopez-Rodriguez, Maria L. .

JOURNAL OF MEDICINAL CHEMISTRY, 2014, 57 (17) :7160-7181

[4] 5-chloro-N-(4-methoxy-3-piperazin-1-yl-phenyl)-3-methyl-2-benzothiophenesulfonamide (SB-271046):: A potent, selective, and orally bioavailable 5-HT6 receptor antagonist [J].

Bromidge, SM ;

Brown, AM ;

Clarke, SE ;

Dodgson, K ;

Gager, T ;

Grassam, HL ;

Jeffrey, PM ;

Joiner, GF ;

King, FD ;

Middlemiss, DN ;

Moss, SF ;

Newman, H ;

Riley, G ;

Routledge, C ;

Wyman, P .

JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (02) :202-205

[5]

Bromidge SM, 2001, ROY SOC CH, P101

[6] Conformationally constrained N1-arylsulfonyltryptamine derivatives as 5-HT6 receptor antagonists [J].

Cole, DC ;

Lennox, WJ ;

Stock, JR ;

Ellingboe, JW ;

Mazandarani, H ;

Smith, DL ;

Zhang, GM ;

Tawa, GJ ;

Schechter, LE .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2005, 15 (21) :4780-4785

[7] Discovery of 5-arylsulfonamido-3(pyrrolidin-2-ylmethyl)-1H-indole derivatives as potent, selective 5-HT6 receptor agonists and antagonists [J].

Cole, DC ;

Lennox, WJ ;

Lombardi, S ;

Ellingboe, JW ;

Bernotas, RC ;

Tawa, GJ ;

Mazandarani, H ;

Smith, DL ;

Zhang, GM ;

Coupet, J ;

Schechter, LE .

JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (02) :353-356

[8] N1-arylsulfonyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives are potent and selective 5-HT6 receptor antagonists [J].

Cole, DC ;

Ellingboe, JW ;

Lennox, WJ ;

Mazandarani, H ;

Smith, DL ;

Stock, JR ;

Zhang, GM ;

Zhou, P ;

Schechter, LE .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2005, 15 (02) :379-383

[9] The cholinergic hypothesis of neuropsychiatric symptoms in Alzheimer's disease [J].

Cummings, JL ;

Back, C .

AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY, 1998, 6 (02) :S64-S78

[10] The 5-HT6 receptor antagonist SB-271046 selectively enhances excitatory neurotransmission in the rat frontal cortex and hippocampus [J].

Dawson, LA ;

Nguyen, HQ ;

Li, P .

NEUROPSYCHOPHARMACOLOGY, 2001, 25 (05) :662-668

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