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

  • Bioorg Med Chem Lett. 2018 Nov 15;28(21):3446-3453. doi: 10.1016/j.bmcl.2018.09.025.
Guozhang Xu  1 ,  Michael D Gaul  2 ,  Gee-Hong Kuo  2 ,  Fuyong Du  2 ,  June Zhi Xu  2 ,  Nathaniel Wallace  2 ,  Simon Hinke  2 ,  Thomas Kirchner  2 ,  Jose Silva  2 ,  Norman D Huebert  2 ,  Seunghun Lee  2 ,  William Murray  2 ,  Yin Liang  2 ,  Keith Demarest  2
Affiliations
  • 1. Discovery Sciences and Cardiovascular & Metabolic Research, Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA. Electronic address: [email protected].
  • 2. Discovery Sciences and Cardiovascular & Metabolic Research, Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA.
PMID: 30268701 DOI: 10.1016/j.bmcl.2018.09.025
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-lactones 3 and 4, which are key intermediates to the C5-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.

Keywords
Bioisostere; C-Aryl glucoside; Diabetes; Glucose transporter; SGLT1 inhibitor; SGLT2 inhibitor.
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