Aminomethylpiperazines as selective urotensin antagonists

被引：12

作者：

Hilfiker, Mark A. ^{[1
]}

Zhang, Daohua ^{[1
]}

Dowdell, Sarah E. ^{[1
]}

Goodman, Krista B. ^{[1
]}

McAtee, John J. ^{[1
]}

Dodson, Jason W. ^{[1
]}

Viet, Andrew Q. ^{[1
]}

Wang, Gren Z. ^{[1
]}

Sehon, Clark A. ^{[1
]}

Behm, David J. ^{[2
]}

Wu, Zining ^{[3
]}

Carballo, Luz H. ^{[3
]}

Douglas, Stephen A. ^{[2
]}

Neeb, Michael J. ^{[1
]}

机构：

[1] GlaxoSmithKline, Dept Med Chem, Cardiovasc & Urogenital Ctr Excellence Drug Disco, King Of Prussia, PA 19406 USA

[2] GlaxoSmithKline, Dept Biol, Cardiovasc & Urogenital Ctr Excellence Drug Disco, King Of Prussia, PA 19406 USA

[3] Screening & Cpds Profiling, Morrisville, NC 27703 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 16期

关键词：

urotensin; piperazine; kappa; opioid; hypertension; 7-TM;

D O I：

10.1016/j.bmcl.2008.07.067

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Aminomethylpiperazines, reported previously as being kappa-opioid receptor agonists, were identified as lead compounds in the development of selective urotensin receptor antagonists. Optimized substitution of the piperazine moiety has provided high affinity urotensin receptor antagonists with greater than 100-fold selectivity over the kappa-Opioid receptor. Select compounds were found to inhibit urotensin-induced vasoconstriction in isolated rat aortic rings consistent with the hypothesis that an urotensin antagonist may be useful for the treatment of hypertension. (c) 2008 Elsevier Ltd. All rights reserved.

引用

页码：4470 / 4473

页数：4

共 45 条

[1] Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14 [J].

Ames, RS ;

Sarau, HM ;

Chambers, JK ;

Willette, RN ;

Alyar, NV ;

Romanic, AM ;

Louden, CS ;

Foley, JJ ;

Sauermelch, CF ;

Coatney, RW ;

Ao, ZH ;

Disa, J ;

Holmes, SD ;

Stadel, JM ;

Martin, JD ;

Liu, WS ;

Glover, GI ;

Wilson, S ;

McNulty, DE ;

Ellis, CE ;

Elshourbagy, NA ;

Shabon, U ;

Trill, JJ ;

Hay, DWP ;

Ohlstein, EH ;

Bergsma, DJ ;

Douglas, SA .

NATURE, 1999, 401 (6750) :282-286

[2] Urotensin-II: a novel systemic hypertensive factor in the cat [J].

Behm, DJ ;

Doe, CPA ;

Johns, DG ;

Maniscalco, K ;

Stankus, GP ;

Wibberley, A ;

Willette, RN ;

Douglas, SA .

NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, 2004, 369 (03) :274-280

[3]

Bern H.A., 1985, Recent Progress in Hormone Research, V41, P533

[4] NEUROPROTECTIVE ACTIONS OF GR89696, A HIGHLY POTENT AND SELECTIVE KAPPA-OPIOID RECEPTOR AGONIST [J].

BIRCH, PJ ;

ROGERS, H ;

HAYES, AG ;

HAYWARD, NJ ;

TYERS, MB ;

SCOPES, DIC ;

NAYLOR, A ;

JUDD, DB .

BRITISH JOURNAL OF PHARMACOLOGY, 1991, 103 (03) :1819-1823

[5] Urotensin II evokes potent vasoconstriction in humans in vivo [J].

Böhm, F ;

Pernow, J .

BRITISH JOURNAL OF PHARMACOLOGY, 2002, 135 (01) :25-27

[6] Increased expression of urotensin II and its cognate receptor GPR14 in atherosclerotic lesions of the human aorta [J].

Bousette, N ;

Patel, L ;

Douglas, SA ;

Ohlstein, EH ;

Giaid, A .

ATHEROSCLEROSIS, 2004, 176 (01) :117-123

[7] New N- and O-arylations with phenylboronic acids and cupric acetate [J].

Chan, DMT ;

Monaco, KL ;

Wang, RP ;

Winters, MP .

TETRAHEDRON LETTERS, 1998, 39 (19) :2933-2936

[8] Plasma concentration of urotensin II is raised in hypertension [J].

Cheung, BMY ;

Leung, R ;

Man, YB ;

Wong, LYF .

JOURNAL OF HYPERTENSION, 2004, 22 (07) :1341-1344

[9] Pharmacology of the urotensin-II receptor antagonist palosuran (ACT-058362; 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea sulfate salt):: First demonstration of a pathophysiological role of the urotensin system [J].

Clozel, M ;

Binkert, C ;

Birker-Robaczewska, M ;

Boukhadra, C ;

Ding, SS ;

Fischli, W ;

Hess, P ;

Mathys, B ;

Morrison, K ;

Müller, C ;

Nayler, O ;

Qiu, CB ;

Rey, M ;

Scherz, MW ;

Velker, J ;

Weller, T ;

Xi, JF ;

Ziltener, P .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2004, 311 (01) :204-212

[10] ENANTIOSPECIFICITY OF KAPPA-RECEPTORS - COMPARISON OF RACEMIC COMPOUNDS AND ACTIVE ENANTIOMERS IN 2 NOVEL SERIES OF KAPPA-AGONIST ANALGESICS [J].

COLLE, R ;

CLARKE, GD ;

DONDIO, G ;

GIARDINA, G ;

PETRONE, G ;

SBACCHI, M ;

VECCHIETTI, V .

CHIRALITY, 1992, 4 (01) :8-15

← 1 2 3 4 5 →