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. Issue 21 (15th November 2018)

• Record Type: Journal Article
• Authors: Xu, Guozhang; Gaul, Michael D.; Kuo, Gee-Hong; Du, Fuyong; Xu, June Zhi; Wallace, Nathaniel; Hinke, Simon; Kirchner, Thomas; Silva, Jose; Huebert, Norman D.; Lee, Seunghun; Murray, William; Liang, Yin; Demarest, Keith
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 21(2018)
• Page Start: 3446
• Page End: 3453
• Publication Date: 2018-11-15
• Subjects: Diabetes -- Glucose transporter -- SGLT1 inhibitor -- SGLT2 inhibitor -- Bioisostere -- C-Aryl glucoside; QUHJWCHBJBZVQP-IDYLKPADSA-N -- BILUNNIHYDMSKS-MJALHYBGSA-N -- BSBHQOFIMOUJAR-MDBOPMCTSA-N -- CADHWTGZCAYZEA-IDYLKPADSA-N -- ADOHIJAAUMSPIL-MJALHYBGSA-N -- QMNFASCAEVCTBD-VOFPXKNKSA-N -- CSNQRNLDJGBNRX-VOFPXKNKSA-N -- MNCHCPLVIYRKIQ-IFPLKCGESA-N -- WNRGYKCIUTVKSP-IFPLKCGESA-N -- VCHMTHOALXARTC-IFPLKCGESA-N -- BLFZECRQISKCID-ZXGKGEBGSA-N -- UUFMYTIFKJBWEE-ZGLCYIBRSA-N -- XVSIMJCIPAKINP-ZXGKGEBGSA-N -- XTPOLJQBQIYEOD-INFWBLCHSA-N -- CKSOHNRJAPWNEW-YSTOQKLRSA-N -- YLILUNGWTMHRGR-FXSWLTOZSA-N -- XJNKZTHFPGIJNS-NXRLNHOXSA-N -- IREUAKAPJGOFFS-LKVPNWEUSA-N -- DRHBOKKRSZVDMB-UKGKTARGSA-N -- SJYPWTPTVJCIPR-ZEBDFXRSSA-N -- PURVYKQYRCVZBC-SJSRKZJXSA-N -- YWUXZYJCAMKKIB-AWGDKMGJSA-N -- FIHYONSINSKFAH-GASJEMHNSA-N -- DPGJKBANJUBLLX-RQICVUQASA-N -- ZOYLXCCDXVFFRQ-ZIQFBCGOSA-N -- CMPXKQSALMCJFZ-FQBWVUSXSA-N -- IARZDNVHPGBKFP-LBELIVKGSA-N -- HAXXWGXTCMQJDQ-RUOAZZEASA-N -- TVMGXKGTVIUPCH-MZIUKZFCSA-N -- NAPQUFCMAIYVQE-UHFFFAOYSA-N -- FLEKTFCWLCGXBE-UHFFFAOYSA-N -- XUSOWRNHQIRVMO-UHFFFAOYSA-N -- AFYPVMNFKSAWQJ-UHFFFAOYSA-N -- HLIVRNMBZJSPRJ-UHFFFAOYSA-N -- ZXGDUCHQUKDACB-QZUUWFBJSA-N -- WGNZPASBEGAWER-ILLQWBKOSA-N -- VWCSTTXGACHXTF-QBTBBBLZSA-N -- JRCJDHHDZPYFFN-MDBOPMCTSA-N; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.09.025
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: A new series of SGLT1 and SGLT2 dual inhibitors were disclosed. Two methods were developed to efficiently synthesize C5 -fluoro-lactones3 and4 . Lead compound2b demonstrated potent hSGLT1 and hSGLT2 inhibition. Lead compound2b showed robust in vivo efficacy in rodent models of diabetes. Abstract: 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 C5 -fluoro-lactones3 and4, which are key intermediates to the C5 -fluoro-hexose based C-aryl glucosides. Compound2b 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.