Design, synthesis and biological evaluation of (2S, 3R, 4R, 5S, 6R)-5-fluoro-6-(hydroxymethyl)-2-aryltetrahydro-2H-pyran-3,4-diols as potent and orally active SGLT dual inhibitors

被引：10

作者：

Xu, Guozhang ^{[1
]}

Gaul, Michael D. ^{[1
]}

Kuo, Gee-Hong ^{[1
]}

Du, Fuyong ^{[1
]}

Xu, June Zhi ^{[1
]}

Wallace, Nathaniel ^{[1
]}

Hinke, Simon ^{[1
]}

Kirchner, Thomas ^{[1
]}

Silva, Jose ^{[1
]}

Huebert, Norman D. ^{[1
]}

Lee, Seunghun ^{[1
]}

Murray, William ^{[1
]}

Liang, Yin ^{[1
]}

Demarest, Keith ^{[1
]}

机构：

[1] Janssen Res & Dev LLC, Discovery Sci & Cardiovasc & Metab Res, Welsh & McKean Rd, Spring House, PA 19477 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2018年 / 28卷 / 21期

关键词：

Diabetes; Glucose transporter; SGLT1; inhibitor; SGLT2; Bioisostere; C-Aryl glucoside; AFFINITY NA+/GLUCOSE COTRANSPORTER; C-GLUCOSIDE; DISCOVERY; TRANSPORT; KIDNEY;

D O I：

10.1016/j.bmcl.2018.09.025

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A new series of (2S, 3R, 4R, 5S, 6R)-5-fluoro-6-(hydroxymethyl)-2-aryltetrahydro-2H-pyran-3,4-diols as dual inhibitors of sodium glucose co-transporter proteins (SGLTs) were disclosed. Two methods were developed to efficiently synthesize C-5-fluoro-lactones 3 and 4, which are key intermediates to the C-5-fluoro-hexose based C-aryl glucosides. Compound 2b demonstrated potent hSGLT1 and hSGLT2 inhibition (IC50 = 43 nM for SGLT1 and IC50 = 9 nM for SGLT2). It showed robust inhibition of blood glucose excursion in oral glucose tolerance test (OGTT) in Sprague Dawley (SD) rats and exerted pronounced antihyperglycemic effects in db/db mice and high-fat diet-fed ZDF rats when dosed orally at 10 mg/kg.

引用

页码：3446 / 3453

页数：8

共 50 条

[31] Stereodivergent synthesis of (2S,3S,4R,5R)- and (2S,3S,4R,5S)-[3,4,5-D3]proline depending on the substituent of the γ-lactam ring
Oba, M
Miyakawa, A
Nishiyama, K
Terauchi, T
Kainosho, M
JOURNAL OF ORGANIC CHEMISTRY, 1999, 64 (25): : 9275 - 9278
[32] SYNTHESIS (2S, 3R, 4R, 6E)-3-HYDROXY-4-METHYL-2-METHYLAMINO-6-OCTENIC ACID
OGORODNICHUK, AS
DYBENKO, AG
ROMANOVA, VP
SHILIN, VV
UKRAINSKII KHIMICHESKII ZHURNAL, 1990, 56 (11): : 1203 - 1205
[33] SYNTHESIS OF (2R,4S,5S)-EPIALLOMUSCARINE, (2S,3R,5S)-ISOEPIALLOMUSCARINE, AND (2S,3S,4S,5S)-3-HYDROXYEPIALLOMUSCARINE FROM ALPHA-D-GLUCOSE
WANG, PC
JOULLIE, MM
JOURNAL OF ORGANIC CHEMISTRY, 1980, 45 (26): : 5359 - 5363
[34] (2S, 3R, 4R, 5R)-2-(tert-butyldimethylsilyloxymethyl)-2,4,5-trimethyltetrahydrofuran-3,4-diol
Fan, HT
Schürmann, M
Preut, H
Krause, N
ACTA CRYSTALLOGRAPHICA SECTION E-CRYSTALLOGRAPHIC COMMUNICATIONS, 2005, 61 : O1987 - O1988
[35] STEREOSPECIFIC SYNTHESIS OF (2S,4R)-[5,5,5-H-2(3)]-LEUCINE
AUGUST, RA
KHAN, JA
MOODY, CM
YOUNG, DW
TETRAHEDRON LETTERS, 1992, 33 (32) : 4617 - 4620
[36] Stereospecific synthesis of (2S,4R)-[5,5,5-H-2(3)]leucine
August, RA
Khan, JA
Moody, CM
Young, DW
JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1, 1996, (06): : 507 - 514
[37] The first stereoselective total synthesis of (3S,4R)-dihydroxy-(6S)-undecyl-α-pyranone and total synthesis of (2S,3R,5S)-(-)-2,3-dihydroxytetradecan-5-olide
Sabitha, Gowravaram
Nayak, Sambit
Bhikshapathi, M.
Yadav, J. S.
TETRAHEDRON LETTERS, 2009, 50 (38) : 5428 - 5429
[38] Stereospecific synthesis of (2S,4R)-[5,5,5-2H3]leucine
J Chem Soc Perkin Trans 1, 6 (507):
[39] Short practical synthesis of (3R,4R,5R,6R)-tetrahydroxyazepane and (3S,4S,5S,6S)-tetrahydroxyazepane from D- and L-chiro-inositol, respectively
Painter, GF
Falshaw, A
JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1, 2000, (07): : 1157 - 1159
[40] 2'3 - 4,5'-DI-O-BENZILIDENE-(2S,5S)-BIS-HYDROXYMETHYL-(3R,4R)-DIHYDROXYTHIOLANE, A CHIRAL AUXILLARY IN METHYLENE TRANSFER-REACTIONS
OGILVIE, WW
DURST, T
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 1988, 195 : 125 - ORGN

← 1 2 3 4 5 →