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

被引：58

作者：

Mathvink, RJ ^{[1
]}

Tolman, JS ^{[1
]}

Chitty, D ^{[1
]}

Candelore, MR ^{[1
]}

Cascieri, MA ^{[1
]}

Colwell, LF ^{[1
]}

Deng, LP ^{[1
]}

Feeney, WP ^{[1
]}

Forrest, MJ ^{[1
]}

Hom, GJ ^{[1
]}

MacIntyre, DE ^{[1
]}

Miller, RR ^{[1
]}

Stearns, RA ^{[1
]}

Tota, L ^{[1
]}

Wyvratt, MJ ^{[1
]}

Fisher, MH ^{[1
]}

Weber, AE ^{[1
]}

机构：

[1] Merck Res Labs, Rahway, NJ 07065 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2000年 / 43卷 / 21期

关键词：

D O I：

10.1021/jm000286i

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

As part of our investigation into the development of orally bioavailable beta (3) adrenergic receptor agonists, we have identified a series of pyridylethanolamine analogues possessing a substituted thiazole benzenesulfonamide pharmacophore that are potent human beta (3) agonists with excellent selectivity against other human beta receptor subtypes. Several of these compounds also exhibited an improved pharmacokinetic profile in dogs. For example, thiazole sulfonamide 2e (R = 4-F3C-C6H4) is a potent full beta (3) agonist (EC50 = 3.6 nM, 94% activation) with >600-fold selectivity over the human beta (1) and beta (2) receptors, which also displays good oral bioavailability in several mammalian species, as well as an extended duration of action.

引用

页码：3832 / 3836

页数：5

共 20 条

[1]

Arch JRS, 1996, INT J OBESITY, V20, P191

[2] 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

[3] Synthesis and SAR of benzyl and phenoxymethylene oxadiazole benzenesulfonamides as selective β3 adrenergic receptor agonist antiobesity agents [J].

Biftu, T ;

Feng, DD ;

Liang, GB ;

Kuo, H ;

Qian, XX ;

Naylor, EM ;

Colandrea, VJ ;

Candelore, MR ;

Cascieri, MA ;

Colwell, LF ;

Forrest, MJ ;

Hom, GJ ;

MacIntyre, DE ;

Stearns, RA ;

Strader, CD ;

Wyvratt, MJ ;

Fisher, MH ;

Weber, AE .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2000, 10 (13) :1431-1434

[4]

BROCKUNIER LL, IN PRESS BIOORG MED

[5]

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

[6] A selective human β3 adrenergic receptor agonist increases metabolic rate in rhesus monkeys [J].

Fisher, MH ;

Amend, AM ;

Bach, TJ ;

Barker, JM ;

Brady, EJ ;

Candelore, MR ;

Carroll, D ;

Cascieri, MA ;

Chiu, SHL ;

Deng, LP ;

Forrest, MJ ;

Hegarty-Friscino, B ;

Guan, XM ;

Hom, GJ ;

Hutchins, JE ;

Kelly, LJ ;

Mathvink, RJ ;

Metzger, JM ;

Miller, RR ;

Ok, HO ;

Parmee, ER ;

Saperstein, R ;

Strader, CD ;

Stearns, RA ;

Thompson, GM ;

Tota, L ;

Vicario, PP ;

Weber, AE ;

Woods, JW ;

Wyvratt, MJ ;

Zafian, PT ;

MacIntyre, DE .

JOURNAL OF CLINICAL INVESTIGATION, 1998, 101 (11) :2387-2393

[7] CLONING OF THE CDNA FOR THE HUMAN BETA-1-ADRENERGIC RECEPTOR [J].

FRIELLE, T ;

COLLINS, S ;

DANIEL, KW ;

CARON, MG ;

LEFKOWITZ, RJ ;

KOBILKA, BK .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1987, 84 (22) :7920-7924

[8] CDNA FOR THE HUMAN BETA-2-ADRENERGIC RECEPTOR - A PROTEIN WITH MULTIPLE MEMBRANE-SPANNING DOMAINS AND ENCODED BY A GENE WHOSE CHROMOSOMAL LOCATION IS SHARED WITH THAT OF THE RECEPTOR FOR PLATELET-DERIVED GROWTH-FACTOR [J].

KOBILKA, BK ;

DIXON, RAF ;

FRIELLE, T ;

DOHLMAN, HG ;

BOLANOWSKI, MA ;

SIGAL, IS ;

YANGFENG, TL ;

FRANCKE, U ;

CARON, MG ;

LEFKOWITZ, RJ .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1987, 84 (01) :46-50

[9] Pharmacological treatment of obesity: Therapeutic strategies [J].

Kordik, CP ;

Reitz, AB .

JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (02) :181-201

[10]

Lowell BB, 1997, ANNU REV MED, V48, P307

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