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

[41] (2R,3R,4R,5S)-3,4,5-trihydroxy-2′(2-hydroxyethyl)piperidinium chloride
Koman, M
Szolcsányi, P
Gracza, T
ACTA CRYSTALLOGRAPHICA SECTION C-CRYSTAL STRUCTURE COMMUNICATIONS, 2000, 56 : E138 - E138
[42] (2R,3R,4R,5S)-3,4,5-Trihydroxy-2-(2-hydroxyethyl)piperidinium chloride
Koman, Marian
Szolcsányi, Peter
Graczab, Tibor
2000, International Union of Crystallography, 5 Abbey Road, Chester, CH1 2HU, United Kingdom (56)
[43] An efficient stereoselective synthesis of Z-(2S)- and Z-(2R)-2-tert-butoxycarbonylamino-6-hydroxyhex-4-enoic acid, key intermediates in the synthesis of (2S,4S,5R)-(-)- and (2R,4R,5S)-(+)-bulgecinine
Holt, KE
Swift, JP
Smith, MEB
Taylor, SJC
McCague, R
TETRAHEDRON LETTERS, 2002, 43 (08) : 1545 - 1548
[44] (4R,6R)-6-(hydroxymethyl)-4-methyltetrahydro-2H-pyran-2-one in the synthesis of polyfunctional compounds with the methyl-branched carbon skeleton
I. V. Mineeva
Russian Journal of Organic Chemistry, 2013, 49 : 253 - 258
[45] (4R,6R)-6-(hydroxymethyl)-4-methyltetrahydro-2H-pyran-2-one in the synthesis of polyfunctional compounds with the methyl-branched carbon skeleton
Mineeva, I. V.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY, 2013, 49 (02) : 253 - 258
[46] REL-(1R,2S,3R,4S,5S,6R,7S,8R)-2,3,6,7-TETRAKIS(CHLOROMETHYL)-1,4-5,8-DIEPOXY-1,2,3,4,5,6,7,8-OCTAHYDROANTHRACENE
KOHNKE, FH
MATHIAS, JP
STODDART, JF
SLAWIN, AMZ
WILLIAMS, DJ
ACTA CRYSTALLOGRAPHICA SECTION C-CRYSTAL STRUCTURE COMMUNICATIONS, 1990, 46 : 1043 - 1046
[47] First stereoselective total synthesis of (6R)-6-[(4R,6R)-4,6-dihydroxy-10-phenyldec-1-enyl]-5,6-dihydro-2H-pyran-2-one
Krishna, Palakodety Radha
Srinivas, Ravula
TETRAHEDRON LETTERS, 2007, 48 (11) : 2013 - 2015
[48] (2S*,3S*,4R*,5R*)-3,4,5-Trihydroxy-6-(hydroxy-methyl)-3,4,5,6-tetrahydro-2H-pyran-2-yl benzoate
He, XJ
Lobkovsky, E
Liu, RH
ACTA CRYSTALLOGRAPHICA SECTION E-CRYSTALLOGRAPHIC COMMUNICATIONS, 2006, 62 : O471 - O472
[49] 6-(Acetoxymethyl)-5-chloro-2-[(2R,3R,4R,5S)-3,4-diacetoxy-2,5-bis(chloromethyl)-2,3,4,5-tetrahydro-furan-2-yloxy]-3,4,5,6-tetrahydro-2H-pyran-3,4-diyl diacetate toluene solvate
Wen, HL
Fang, ZJ
Wu, ZS
Xie, MY
ACTA CRYSTALLOGRAPHICA SECTION E-STRUCTURE REPORTS ONLINE, 2006, 62 : O1157 - O1159
[50] (3R,4S,5S)-4-hydroxy-3-methyl-5-[(2S,3R)-3-methylpent-4-en-2-yl] tetrahydrofuran-2-one
Becker, Annika
Schuermann, Markus
Preut, Hans
Hiersemann, Martin
ACTA CRYSTALLOGRAPHICA SECTION E-STRUCTURE REPORTS ONLINE, 2008, 64 : O1517 - U2536

← 1 2 3 4 5 →