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

Guozhang Xu; Michael D Gaul; Gee-Hong Kuo; Fuyong Du; June Zhi Xu; Nathaniel Wallace; Simon Hinke; Thomas Kirchner; Jose Silva; Norman D Huebert; Seunghun Lee; William Murray; Yin Liang; Keith Demarest

doi:10.1016/j.bmcl.2018.09.025

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. Epub 2018 Sep 19.

Authors

Affiliations

¹ Discovery Sciences and Cardiovascular & Metabolic Research, Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA. Electronic address: gxu4@its.jnj.com.
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.

MeSH terms

Administration, Oral
Animals
Blood Glucose / drug effects
Deoxyglucose / administration & dosage
Deoxyglucose / analogs & derivatives
Deoxyglucose / chemical synthesis
Deoxyglucose / therapeutic use*
Diabetes Mellitus, Experimental / drug therapy*
Drug Design
Humans
Hypoglycemic Agents / administration & dosage
Hypoglycemic Agents / chemical synthesis
Hypoglycemic Agents / chemistry
Hypoglycemic Agents / therapeutic use*
Macaca fascicularis
Male
Mice
Microsomes, Liver / metabolism
Molecular Structure
Rats, Sprague-Dawley
Rats, Zucker
Sodium-Glucose Transporter 1 / antagonists & inhibitors*
Sodium-Glucose Transporter 2 / metabolism
Sodium-Glucose Transporter 2 Inhibitors / administration & dosage
Sodium-Glucose Transporter 2 Inhibitors / chemical synthesis
Sodium-Glucose Transporter 2 Inhibitors / chemistry
Sodium-Glucose Transporter 2 Inhibitors / therapeutic use*
Structure-Activity Relationship

Substances

Blood Glucose
Hypoglycemic Agents
SLC5A1 protein, human
SLC5A2 protein, human
Sodium-Glucose Transporter 1
Sodium-Glucose Transporter 2
Sodium-Glucose Transporter 2 Inhibitors
Deoxyglucose