Discovery of GCC5694A: A potent and selective sodium glucose co-transporter 2 inhibitor for the treatment of type 2 diabetes

Young Kyu Kong; Kwang-Seop Song; Myung Eun Jung; Misuk Kang; Hyeon Jung Kim; Min Ju Kim

doi:10.1016/j.bmcl.2021.128466

Discovery of GCC5694A: A potent and selective sodium glucose co-transporter 2 inhibitor for the treatment of type 2 diabetes

Bioorg Med Chem Lett. 2022 Jan 15:56:128466. doi: 10.1016/j.bmcl.2021.128466. Epub 2021 Nov 20.

Authors

Young Kyu Kong¹, Kwang-Seop Song², Myung Eun Jung¹, Misuk Kang¹, Hyeon Jung Kim¹, Min Ju Kim³

Affiliations

¹ Department of Research and Early Development, GC Pharma, Gyeonggi-do, Republic of Korea.
² Department of Manufacturing Science & Technology, GC Pharma, Chungcheongbuk-do, Republic of Korea.
³ R&D Division, GC Pharma, Gyeonggi-do, Republic of Korea. Electronic address: metilred@gccorp.com.

PMID: 34813882
DOI: 10.1016/j.bmcl.2021.128466

Abstract

Sodium-dependent glucose co-transporter 2 (SGLT2) has emerged as a promising drug target for the treatment of type 2 diabetes, and recently, several SGLT2 inhibitors have been approved for clinical use. A series of molecules with a C-aryl glucoside scaffold was designed and synthesized for biological evaluation. Among the molecules tested, a dihydrobenzofuran-containing analog, 14g (GCC5694A), exhibited excellentin vitro activity against SGLT2 (IC₅₀ = 0.460 nM), good selectivity for SGLT1, and good metabolic stability. Data from further evaluation of the compound in animal models showed that this molecule is a promising candidate for development as an anti-diabetic agent.

Keywords: Dapagliflozin; Diabetes; Dihydrobenzofuran; Glucoside; SGLT.

Publication types

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

MeSH terms

Administration, Oral
Animals
Diabetes Mellitus, Experimental / chemically induced
Diabetes Mellitus, Experimental / drug therapy*
Diabetes Mellitus, Experimental / metabolism
Diabetes Mellitus, Type 2 / chemically induced
Diabetes Mellitus, Type 2 / drug therapy*
Diabetes Mellitus, Type 2 / metabolism
Dose-Response Relationship, Drug
Drug Discovery*
Humans
Molecular Structure
Rats
Rats, Sprague-Dawley
Sodium-Glucose Transporter 2 / metabolism*
Sodium-Glucose Transporter 2 Inhibitors / administration & dosage
Sodium-Glucose Transporter 2 Inhibitors / chemistry
Sodium-Glucose Transporter 2 Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

SLC5A2 protein, human
Slc5a2 protein, rat
Sodium-Glucose Transporter 2
Sodium-Glucose Transporter 2 Inhibitors