Discovery of potent and orally bioavailable heterocycle-based β3-adrenergic receptor agonists, potential therapeutics for the treatment of obesity

被引：19

作者：

Lafontaine, Jennifer A.

Day, Robert F.

Dibrino, Joe

Hadcock, John R.

Hargrove, Diane M.

Linhares, Michael

Martin, Kelly A.

Maurer, Tristan S.

Nardone, Nancy A.

Tess, David A.

DaSilva-Jardine, Paul

机构：

[1] Pfizer Global Res & Dev, Dept Cardiovasc & Metab Dis, Groton, CT 06340 USA

[2] Pfizer Global Res & Dev, Dept Pharmacokinet Dynam & Metab, La Jolla, CA 92121 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2007年 / 17卷 / 18期

关键词：

beta(3)-adrenergic receptor agonists; obesity; thermogenesis;

D O I：

10.1016/j.bmcl.2007.06.072

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel series of heterocycle-based analogs were prepared and evaluated for their in vitro and in vivo biological activity as human beta(3)-adrenergic receptor (AR) agonists. Several analogs demonstrated potent agonist activity at the beta(3)-AR, functional selectivity against beta(1)- and beta(2)-ARs, and favorable pharmacokinetic profiles in vivo. Compound 17 increased oxygen consumption in rats, a measure of energy expenditure, with an EDO20% of 2 mg/kg. (c) 2007 Elsevier Ltd. All rights reserved.

引用

收藏

页码：5245 / 5250

页数：6

相关论文

共 20 条

[1] ATYPICAL BETA-ADRENOCEPTOR ON BROWN ADIPOCYTES AS TARGET FOR ANTI-OBESITY DRUGS [J].

ARCH, JRS ;

AINSWORTH, AT ;

CAWTHORNE, MA ;

PIERCY, V ;

SENNITT, MV ;

THODY, VE ;

WILSON, C ;

WILSON, S .

NATURE, 1984, 309 (5964) :163-165

[2] USE OF THE PAULING OXYGEN ANALYZER FOR MEASUREMENT OF OXYGEN CONSUMPTION OF ANIMALS IN OPEN-CIRCUIT SYSTEMS AND IN A SHORT-LAG, CLOSED-CIRCUIT APPARATUS [J].

DEPOCAS, F ;

HART, JS .

JOURNAL OF APPLIED PHYSIOLOGY, 1957, 10 (03) :388-392

[3]

Dow R L, 1997, Expert Opin Investig Drugs, V6, P1811, DOI 10.1517/13543784.6.12.1811

[4]

DOW RL, 2001, Patent No. 1138685

[5] Potent benzimidazolone based human β3-adrenergic receptor agonists [J].

Finley, Don R. ;

Bell, Michael G. ;

Borel, Anthony G. ;

Bloomquist, William E. ;

Cohen, Marlene L. ;

Heiman, Mark. L. ;

Kriauciunas, Aidas ;

Matthews, Donald P. ;

Miles, Tania ;

Neel, David A. ;

Rito, Christopher J. ;

Sall, Daniel J. ;

Shuker, Anthony J. ;

Stephens, Thomas W. ;

Tinsley, Frank C. ;

Winter, Mark A. ;

Jesudason, Cynthia D. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (21) :5691-5694

[6]

Howe Ralph, 1993, Drugs of the Future, V18, P529

[7] SYNTHESIS OF BROMOACETYL DERIVATIVES BY USE OF TETRABUTYLAMMONIUM TRIBROMIDE [J].

KAJIGAESHI, S ;

KAKINAMI, T ;

OKAMOTO, T ;

FUJISAKI, S .

BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN, 1987, 60 (03) :1159-1160

[8]

LAFONTAINE JA, 2003, Patent No. 2003072572

[9] Discovery of a potent, orally bioavailable β3 adrenergic receptor agonist, (R)-N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-[4-(trifluoromethyl)phenyl]thiazol-2-yl]benzenesulfonamide [J].

Mathvink, RJ ;

Tolman, JS ;

Chitty, D ;

Candelore, MR ;

Cascieri, MA ;

Colwell, LF ;

Deng, LP ;

Feeney, WP ;

Forrest, MJ ;

Hom, GJ ;

MacIntyre, DE ;

Miller, RR ;

Stearns, RA ;

Tota, L ;

Wyvratt, MJ ;

Fisher, MH ;

Weber, AE .

JOURNAL OF MEDICINAL CHEMISTRY, 2000, 43 (21) :3832-3836

[10] THE USE OF DIETHYL AZODICARBOXYLATE AND TRIPHENYLPHOSPHINE IN SYNTHESIS AND TRANSFORMATION OF NATURAL-PRODUCTS [J].

MITSUNOBU, O .

SYNTHESIS-STUTTGART, 1981, (01) :1-28