Design, synthesis and biological activity of novel dimethyl-{2-[6-substituted-indol-1-yl]-ethyl}-amine as potent, selective, and orally-bioavailable 5-HT1D agonists

被引：6

作者：

Isaac, M

Slassi, M

Xin, T

Arora, J

O'Brien, A

Edwards, L

MacLean, N

Wilson, J

Demschyshyn, L

Labrie, P

Naismith, A

Maddaford, S

Papac, D

Harrison, S

Wang, H

Draper, S

Tehim, A

机构：

[1] NPS Pharmaceut Inc, Mississauga, ON L4V 1V7, Canada

[2] NPS Pharmaceut Inc, Salt Lake City, UT 84108 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2003年 / 13卷 / 24期

关键词：

D O I：

10.1016/j.bmcl.2003.09.025

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel series of highly potent human 5-HT1D agonists, dimethyl-{2-[6-substituted-indol-1-yl]-ethyl}-amine, was synthesized. Structure-activity relationship (SAR) investigation revealed 4-[1-(2-dimethylamino-ethyl)-1H-indol-6-yl]-tetrahydro-thiopyran-4-ol, 11b (ALX-2732), as a potent (K-i = 2.4 nM) agonist at the human 5-HT1D receptor with good selectivity over the other serotonin receptor subtypes. This compound demonstrated favorable in vitro metabolic stability in human and rat liver microsomes and was found to be orally bioavailable in rats (F-po = 51%) (C) 2003 Elsevier Ltd. All rights reserved.

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收藏

页码：4409 / 4413

页数：5

相关论文

共 15 条

[1] Isochroman-6-carboxamides as highly selective 5-HT1D agonists:: Potential new treatment for migraine without cardiovascular side effects [J].

Ennis, MD ;

Ghazal, NB ;

Hoffman, RL ;

Smith, MW ;

Schlachter, SK ;

Lawson, CF ;

Bin Im, W ;

Pregenzer, JF ;

Svensson, KA ;

Lewis, RA ;

Hall, ED ;

Sutter, DM ;

Harris, LT ;

McCall, RB .

JOURNAL OF MEDICINAL CHEMISTRY, 1998, 41 (13) :2180-2183

[2] SPECIES-DIFFERENCES IN THE PHARMACOLOGY OF TERMINAL 5-HT AUTORECEPTORS IN MAMMALIAN BRAIN [J].

HOYER, D ;

MIDDLEMISS, DN .

TRENDS IN PHARMACOLOGICAL SCIENCES, 1989, 10 (04) :130-132

[3]

Isaac M, 2001, IDrugs, V4, P189

[4] Differential distribution of 5HT1D- and 5HT1B-immunoreactivity within the human trigemino-cerebrovascular system:: Implications for the discovery of new antimigraine drugs [J].

Longmore, J ;

Shaw, D ;

Smith, D ;

Hopkins, R ;

McAllister, G ;

Pickard, JD ;

Sirinathsinghji, DJS ;

Butler, AJ ;

Hill, RG .

CEPHALALGIA, 1997, 17 (08) :833-842

[5]

Longmore J., 1999, CURR OPIN CPNS INVES, V1, P39

[6] RELEASE-REGULATING SEROTONIN 5-HT1D AUTORECEPTORS IN HUMAN CEREBRAL-CORTEX [J].

MAURA, G ;

THELLUNG, S ;

ANDRIOLI, GC ;

RUELLE, A ;

RAITERI, M .

JOURNAL OF NEUROCHEMISTRY, 1993, 60 (03) :1179-1182

[7] Preclinical studies characterizing the anti-migraine and cardiovascular effects of the selective 5-HT1D receptor agonist PNU-142633 [J].

McCall, RB ;

Huff, R ;

Chio, CL ;

TenBrink, R ;

Bergh, CL ;

Ennis, MD ;

Ghazal, NB ;

Hoffman, RL ;

Meisheri, K ;

Higdon, NR ;

Hall, E .

CEPHALALGIA, 2002, 22 (10) :799-806

[8] Synthesis of N-arylpiperazines from aryl halides and piperazine under a palladium tri-tert-butylphosphine catalyst [J].

Nishiyama, M ;

Yamamoto, T ;

Koie, Y .

TETRAHEDRON LETTERS, 1998, 39 (07) :617-620

[9] Decreased sensitivity of 5-HT1D receptors in chronic tension-type headache [J].

Rainero, I ;

Valfrè, W ;

Savi, L ;

Ferrero, M ;

Del Rizzo, P ;

Limone, P ;

Isaia, GC ;

Gianotti, L ;

Pollo, A ;

Verde, R ;

Benedetti, F ;

Pinessi, L .

HEADACHE, 2002, 42 (08) :709-714

[10] 3-[3-(Piperidin-1-yl)propyl] indoles as highly selective h5-HT1D receptor agonists [J].

Russell, MGN ;

Matassa, VG ;

Pengilley, RR ;

van Niel, MB ;

Sohal, B ;

Watt, AP ;

Hitzel, L ;

Beer, MS ;

Stanton, JA ;

Broughton, HB ;

Castro, JL .

JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (24) :4981-5001