5,5-Difluoro- and 5-Fluoro-5-methyl-hexose-based C-Glucosides as potent and orally bioavailable SGLT1 and SGLT2 dual inhibitors

Guozhang Xu; Fuyong Du; Gee-Hong Kuo; June Zhi Xu; Yin Liang; Keith Demarest; Michael D Gaul

doi:10.1016/j.bmcl.2020.127387

5,5-Difluoro- and 5-Fluoro-5-methyl-hexose-based C-Glucosides as potent and orally bioavailable SGLT1 and SGLT2 dual inhibitors

Bioorg Med Chem Lett. 2020 Sep 1;30(17):127387. doi: 10.1016/j.bmcl.2020.127387. Epub 2020 Jul 5.

Authors

Guozhang Xu¹, Fuyong Du², Gee-Hong Kuo³, June Zhi Xu², Yin Liang², Keith Demarest², Michael D Gaul³

Affiliations

¹ Discovery Sciences and Metabolic Research, Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, United States. Electronic address: gxu4@its.jnj.com.
² Cardiovascular & Metabolic Research, Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, United States.
³ Discovery Sciences and Metabolic Research, Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, United States.

PMID: 32738984
DOI: 10.1016/j.bmcl.2020.127387

Abstract

(2S,3R,4R,5S,6R)-2-Aryl-5,5-difluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diols and (2S,3R,4R,5S,6R)-2-aryl-5-fluoro-5-methyl-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diols were discovered as dual inhibitors of sodium glucose co-transporter proteins (e.g. SGLT1 and SGLT2) through rational drug design, efficient synthesis, and in vitro and in vivo evaluation. Compound 6g demonstrated potent dual inhibitory activities (IC₅₀ = 96 nM for SGLT1 and IC₅₀ = 1.3 nM for SGLT2). It showed robust inhibition of blood glucose excursion in an oral glucose tolerance test (OGTT) in Sprague Dawley (SD) rats when dosed at both 1 mg/kg and 10 mg/kg orally. It also demonstrated postprandial glucose control in db/db mice when dosed orally at 10 mg/kg.

Keywords: Bioisostere; C-Aryl Glucoside; Diabetes; Fluorination; Glucose transporter; SGLT1 inhibitor; SGLT2 inhibitor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blood Glucose / analysis
Diabetes Mellitus / drug therapy
Diabetes Mellitus / pathology
Disease Models, Animal
Drug Design
Glucose Tolerance Test
Glucosides / chemistry*
Glucosides / metabolism
Glucosides / pharmacology
Glucosides / therapeutic use
Half-Life
Halogenation
Humans
Hypoglycemic Agents / chemistry*
Hypoglycemic Agents / metabolism
Hypoglycemic Agents / pharmacology
Hypoglycemic Agents / therapeutic use
Inhibitory Concentration 50
Mice
Mice, Inbred C57BL
Microsomes / metabolism
Rats
Rats, Sprague-Dawley
Sodium-Glucose Transporter 1 / antagonists & inhibitors*
Sodium-Glucose Transporter 1 / metabolism
Sodium-Glucose Transporter 2 / chemistry*
Sodium-Glucose Transporter 2 / metabolism*
Structure-Activity Relationship

Substances

Blood Glucose
Glucosides
Hypoglycemic Agents
Sodium-Glucose Transporter 1
Sodium-Glucose Transporter 2