Discovery of diacylphloroglucinols as a new class of GPR40 (FFAR1) agonists

被引：34

作者：

Bharate, Sandip B. ^{[1
]}

Rodge, Atish ^{[1
]}

Joshi, Rajendra K. ^{[3
]}

Kaur, Jaspreet ^{[3
]}

Srinivasan, Shaila ^{[3
]}

Kumar, S. Senthil ^{[2
]}

Kulkarni-Almeida, Asha ^{[2
]}

Balachandran, Sarala ^{[1
]}

Balakrishnan, Arun ^{[2
]}

Vishwakarma, Ram A. ^{[1
]}

机构：

[1] Piramal Life Sci Ltd, Dept Med Chem, Bombay 400063, Maharashtra, India

[2] Piramal Life Sci Ltd, Dept Screening & Biotechnol, Bombay 400063, Maharashtra, India

[3] Piramal Life Sci Ltd, Dept Pharmacol, Bombay 400063, Maharashtra, India

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 24期

关键词：

Diacylphloroglucinols; FFAR1; agonist; GPR40; Type-2; diabetes;

D O I：

10.1016/j.bmcl.2008.10.085

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

In this letter, we report discovery of diacylphloroglucinol compounds as a new class of GPR40 (FFAR1) agonists. Several diacylphloroglucinols with varying length of acyl functionality and substitution on aromatic hydroxyls were synthesized and evaluated for GPR40 agonism using functional calcium-flux assay. Out of 17 compounds evaluated, 14, 17, 19 and 25 exhibited good GPR40 agonistic activity with EC(50) values ranging from 0.07 to 8 mu M (pEC(50) 7.12-5.09), respectively, with maximal agonistic response of 84-102%. (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：6357 / 6361

页数：5

共 31 条

[11] Synthesis and activity of small molecule GPR40 agonists [J].

Garrido, DM ;

Corbett, DF ;

Dwornik, KA ;

Goetz, AS ;

Littleton, TR ;

McKeown, SC ;

Mills, WY ;

Smalley, TL ;

Briscoe, CP ;

Peat, AJ .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (07) :1840-1845

[12]

GE M, 2007, Patent No. 2007136572

[13] Discovery of new G protein-coupled receptors for lipid mediators [J].

Im, DS .

JOURNAL OF LIPID RESEARCH, 2004, 45 (03) :410-418

[14] Free fatty acids regulate insulin secretion from pancreatic β cells through GPR40 [J].

Itoh, Y ;

Kawamata, Y ;

Harada, M ;

Kobayashi, M ;

Fujii, R ;

Fukusumi, S ;

Ogi, K ;

Hosoya, M ;

Tanaka, Y ;

Uejima, H ;

Tanaka, H ;

Maruyama, M ;

Satoh, R ;

Okubo, S ;

Kizawa, H ;

Komatsu, H ;

Matsumura, F ;

Noguchi, Y ;

Shinobara, T ;

Hinuma, S ;

Fujisawa, Y ;

Fujino, M .

NATURE, 2003, 422 (6928) :173-176

[15] G-protein-coupled receptors at a glance [J].

Kroeze, WK ;

Sheffler, DJ ;

Roth, BL .

JOURNAL OF CELL SCIENCE, 2003, 116 (24) :4867-4869

[16] Solid phase synthesis and SAR of small molecule agonists for the GPR40 receptor [J].

McKeown, Stephen C. ;

Corbett, David F. ;

Goetz, Aaron S. ;

Littleton, Thomas R. ;

Bigham, Eric ;

Briscoe, Celia P. ;

Peat, Andrew J. ;

Watson, Steve P. ;

Hickey, Deirdre M. B. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2007, 17 (06) :1584-1589

[17] MACROCARPALS, ANTIBACTERIAL COMPOUNDS FROM EUCALYPTUS, INHIBIT ALDOSE REDUCTASE [J].

MURATA, M ;

YAMAKOSHI, Y ;

HOMMA, S ;

ARAI, K ;

NAKAMURA, Y .

BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY, 1992, 56 (12) :2062-2063

[18]

Negoro K., 2007, [No title captured], Patent No. [WO 2007/123225, 2007123225]

[19] A new phloroglucinol derivative from the brown alga Eisenia bicyclis:: Potential for the effective treatment of diabetic complications [J].

Okada, Y ;

Ishimaru, A ;

Suzuki, R ;

Okuyama, T .

JOURNAL OF NATURAL PRODUCTS, 2004, 67 (01) :103-105

[20]

OWMAN C, 2007, Patent No. 2007049050

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