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

[11] Studies on the transformation of nitrosugars into iminosugars III: synthesis of (2R,3R,4R,5R,6R)-2-(hydroxymethyl)azepane-3,4,5,6-tetraol and (2R,3R,4R,5R,6S)-2-(hydroxymethyl)azepane-3,4,5,6-tetraol
Estevez, Amalia M.
Soengas, Raquel G.
Otero, Jose M.
Estevez, Juan C.
Nash, Robert J.
Estevez, Ramon J.
TETRAHEDRON-ASYMMETRY, 2010, 21 (01) : 21 - 26
[12] Synthesis of (2R,3R,4S,5R,6R)-2-hydroxy-6-(hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triyl tris( 2-methylpropanoate)
Workman, Stephen P.
Fultz, Micheal W.
Liedl, Barbara E.
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2013, 245
[13] (2S,3R,6R)-2-[(R)-1-Hydroxyallyl]-4,4-dimethoxy-6-methyltetrahydro-2H-pyran-3-ol
Bennett, Jack
Murphy, Paul, V
MOLBANK, 2020, 2020 (02) : 1 - 5
[14] Toward a scalable asymmetric synthesis of (4R,5S,6R) Trihydroxycyclohexen-2-one
Rosenberg, Ashley
McIntosh, Matt
Clay, David
Gibson, Andrew
Williams, David
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2011, 242
[15] A NEW SYNTHESIS OF (2S,3R,4R)-2-(HYDROXYMETHYL)PYRROLIDINE-3,4-DIOL
MENG, QC
HESSE, M
HELVETICA CHIMICA ACTA, 1991, 74 (02) : 445 - 450
[16] CYCLIC DIPEPTIDES - A STEREOCONTROLLED SYNTHESIS OF (2S,3R,6R) AND (2R,3R,6R)-6-TERT-BUTOXYCARBONYLAMINO-3-METHOXYCARBONYL-2-METHYL-5-OXOPERHYDRO-1,4-THIAZEPINE
CORELLI, F
CRESCENZA, A
DEI, D
TADDEI, M
BOTTA, M
TETRAHEDRON-ASYMMETRY, 1994, 5 (08) : 1469 - 1472
[17] SYNTHESIS OF (1S 2R 4R 5S 6R)-1,2,4,5,6-PENTA-O-BENZOYLMYOINOSITOL
MERCIER, D
GERO, SD
TETRAHEDRON LETTERS, 1968, (31) : 3459 - &
[18] An efficient stereoselective synthesis of (2S,4S,5R)-(-)- and (2R,4R,5S)-(+)-bulgecinine
Chavan, SP
Praveen, C
Sharma, P
Kalkote, UR
TETRAHEDRON LETTERS, 2005, 46 (03) : 439 - 441
[19] SYNTHESIS OF (2S,5S)-BISHYDROXYMETHYL-(3R,4R)-BISHYDROXYPYRROLIDINE FROM D-MANNITOL
SHING, TKM
TETRAHEDRON, 1988, 44 (23) : 7261 - 7264
[20] (6R)-2-tert-Butyl-6-[(4R,5S)-3-isopropyl-4-methyl-5-phenyloxazolidin-2-yl]phenol
Koyanagi, Takaoki
Edler, Kate L.
Parrott, Raleigh W., II
Hitchcock, Shawn R.
Ferrence, Gregory M.
ACTA CRYSTALLOGRAPHICA SECTION E-STRUCTURE REPORTS ONLINE, 2010, 66 : O898 - U2894

← 1 2 3 4 5 →