Discovery of the first nonpeptide agonist of the GPR14/urotensin-II receptor: 3-(4-chloropheny)-3-(2-(dimethylamino)ethyl)isochroman-1-one (AC-7954)

被引：58

作者：

Croston, GE

Olsson, R

Currier, EA

Burstein, ES

Weiner, D

Nash, N

Severance, D

Allenmark, SG

Thunberg, L

Ma, JN

Mohell, N

O'Dowd, B

Brann, MR

Hacksell, U

机构：

[1] ACADIA Pharmaceut Inc, San Diego, CA 92121 USA

[2] Univ Gothenburg, Dept Chem, SE-41296 Gothenburg, Sweden

[3] Univ Toronto, Dept Pharmacol, Toronto, ON M5S 1A8, Canada

[4] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2002年 / 45卷 / 23期

关键词：

D O I：

10.1021/jm025551+

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A functional cell-based screen identified 3-(4-chlorophenyl)-3-(2-(dimethylamino)ethyl)isochroman-1-one hydrochloride (AC-7954, 1) as a nonpeptidic agonist of the urotensin-II receptor. Racemic 1 had an EC50 of 300 nM at the human UII receptor and was highly selective. Testing of the enantiopure (+)- and (-)- 1 revealed that the UII receptor activity of racemic 1 resides primarily in (+)-1. Being a selective nonpeptidic druglike UII receptor agonist, (+)-1 will be useful as a pharmacological research tool and a potential drug lead.

引用

收藏

页码：4950 / 4953

页数：4

相关论文

共 20 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] NMR AND DYNAMICAL SIMULATED ANNEALING STUDIES ON THE SOLUTION CONFORMATION OF UROTENSIN-II [J].

BHASKARAN, R ;

ARUNKUMAR, AI ;

YU, C .

BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, 1994, 1199 (02) :115-122

[3] Therapeutic and chemical developments of cholecystokinin receptor ligands [J].

de Tullio, P ;

Delarge, J ;

Pirotte, B .

EXPERT OPINION ON INVESTIGATIONAL DRUGS, 2000, 9 (01) :129-146

[4] Human urotensin-II, the most potent mammalian vasoconstrictor identified to date, as a therapeutic target for the management of cardiovascular disease [J].

Douglas, SA ;

Ohlstein, EH .

TRENDS IN CARDIOVASCULAR MEDICINE, 2000, 10 (06) :229-237

[5] Identification of nonpeptidic urotensin II receptor antagonists by virtual screening based on a pharmacophore model derived from structure-activity relationships and nuclear magnetic resonance studies on urotensin II [J].

Flohr, S ;

Kurz, M ;

Kostenis, E ;

Brkovich, A ;

Fournier, A ;

Klabunde, T .

JOURNAL OF MEDICINAL CHEMISTRY, 2002, 45 (09) :1799-1805

[6]

HOULIHAN WJ, 1975, Patent No. 3880885

[7] CONTRACTION OF MAJOR ARTERY SEGMENTS OF RAT BY FISH NEUROPEPTIDE UROTENSIN-II [J].

ITOH, H ;

ITOH, Y ;

RIVIER, J ;

LEDERIS, K .

AMERICAN JOURNAL OF PHYSIOLOGY, 1987, 252 (02) :R361-R366

[8] Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings (Reprinted from Advanced Drug Delivery Reviews, vol 23, pg 3-25, 1997) [J].

Lipinski, CA ;

Lombardo, F ;

Dominy, BW ;

Feeney, PJ .

ADVANCED DRUG DELIVERY REVIEWS, 2001, 46 (1-3) :3-26

[9] Identification of urotensin II as the endogenous ligand for the orphan G-protein-coupled receptor GPR14 [J].

Liu, QY ;

Pong, SS ;

Zeng, ZZ ;

Zhang, Q ;

Howard, AD ;

Williams, DL ;

Davidoff, M ;

Wang, RP ;

Austin, CP ;

McDonald, TP ;

Bai, C ;

George, SR ;

Evans, JF ;

Caskey, CT .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1999, 266 (01) :174-178

[10] CLONING AND CHROMOSOMAL MAPPING OF 3 NOVEL GENES, GPR9, GPR10, AND GPR14 ENCODING RECEPTORS RELATED TO INTERLEUKIN-8, NEUROPEPTIDE-Y, AND SOMATOSTATIN RECEPTORS [J].

MARCHESE, A ;

HEIBER, M ;

NGUYEN, T ;

HENG, HHQ ;

SALDIVIA, VR ;

CHENG, R ;

MURPHY, PM ;

TSUI, LC ;

SHI, XM ;

GREGOR, P ;

GEORGE, SR ;

ODOWD, BF ;

DOCHERTY, JM .

GENOMICS, 1995, 29 (02) :335-344