4-aminopiperidine ureas as potent selective agonists of the human β3-adrenergic receptor

被引：18

作者：

Ashwell, MA

Solvibile, WR

Han, S

Largis, E

Mulvey, R

Tillet, J

机构：

[1] Chemical Sciences, Wyeth-Ayerst Research

[2] Cardiovascular/Metabolic Diseases Research, Wyeth-Ayerst Research

[3] Woburn, MA 01801

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2001年 / 11卷 / 24期

关键词：

D O I：

10.1016/S0960-894X(01)00645-X

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The preparation and structure-activity relationships (SARs) of potent agonists of the human beta (3)-adrenergic receptor (AR) derived from a 4-aminopiperidine scaffold are described. Examples combine human beta (3)-AR potency with selectivity over human beta (1)-AR and/or human beta (2)-AR agonism. Compound 29s was identified as a potent (EC50= 1 nM) and selective (greater than 400-fold over beta (1)- with no beta (2)-AR agonism) full beta (3)-AR agonist with in vivo activity in a transgenic mouse model of thermogenesis. (C) 2001 Elsevier Science Ltd. All rights reserved.

引用

页码：3123 / 3127

页数：5

共 13 条

[1]

ASHWELL MA, 2000, UNPUB JUL

[2]

Belley L. J., 1996, WO Patent, Patent No. [WO9604233, 09604233]

[3] Synthesis and evaluation of (S)-4-(3-(2'-[C-11]isopropylamino)-2-hydroxy-propoxy)-2H-benzimidazol-2-one ((S)-[C-11]CGP 12388) and (S)-4-(3-((1'-[F-18]-fluoroisopropyl)amino)-2-hydroxypropoxy)-2H-benzimidazol-2-one ((S)-[F-18]Fluoro-CGP 12388) for visualization of beta-adrenoceptors with positron emission tomography [J].

Elsinga, PH ;

vanWaarde, A ;

Jaeggi, KA ;

Schreiber, G ;

Heldoorn, M ;

Vaalburg, W .

JOURNAL OF MEDICINAL CHEMISTRY, 1997, 40 (23) :3829-3835

[4] ANTIDIABETIC AND ANTIOBESITY EFFECTS OF A HIGHLY SELECTIVE BETA(3)-ADRENOCEPTOR AGONIST (CL-316,243) [J].

LARGIS, EE ;

BURNS, MG ;

MUENKEL, HA ;

DOLAN, JA ;

CLAUS, TH .

DRUG DEVELOPMENT RESEARCH, 1994, 32 (02) :69-76

[5] MOLECULAR-CLONING OF A HUMAN BETA-3-ADRENERGIC RECEPTOR CDNA [J].

LELIAS, JM ;

KAGHAD, M ;

RODRIGUEZ, M ;

CHALON, P ;

BONNIN, J ;

DUPRE, I ;

DELPECH, B ;

BENSAID, M ;

LEFUR, G ;

FERRARA, P ;

CAPUT, D .

FEBS LETTERS, 1993, 324 (02) :127-130

[6]

MERCK CO INC, 1994, Patent No. 611003

[7] MIXED METHYL SILYL KETALS OF QUINONES - THEIR PREPARATION VIA ANODIC-OXIDATION AND THEIR CHEMISTRY [J].

STERN, A ;

SWENTON, JS .

JOURNAL OF ORGANIC CHEMISTRY, 1987, 52 (13) :2763-2768

[8] TARGETED DISRUPTION OF THE BETA(3)-ADRENERGIC RECEPTOR GENE [J].

SUSULIC, VS ;

FREDERICH, RC ;

LAWITTS, J ;

TOZZO, E ;

KAHN, BB ;

HARPER, ME ;

HIMMSHAGEN, J ;

FLIER, JS ;

LOWELL, BB .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (49) :29483-29492

[9]

Takeda M, 1999, J PHARMACOL EXP THER, V288, P1367

[10]

TOMINAGA M, 1981, CHEM PHARM BULL, V29, P2166

← 1 2 →