5,5-Difluoro- and 5-Fluoro-5-methyl-hexose-based C-Glucosides as potent and orally bioavailable SGLT1 and SGLT2 dual inhibitors |
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| Institution: | 1. Discovery Sciences and Metabolic Research, Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, United States;2. Cardiovascular & Metabolic Research, Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, United States;1. Research and Early Development, Bristol Myers Squibb Company, Princeton, NJ 08543-4000, United States;2. Bristol Myers Squibb-Biocon Research Center, Bangalore, India;1. Pharmaceutical Sciences Laboratories, Research Headquarters, Taisho Pharmaceutical Co., Ltd., Saitama, Japan;2. Discovery Research Laboratories, Research Headquarters, Taisho Pharmaceutical Co., Ltd., Saitama, Japan;3. Drug Safety and Pharmacokinetics Laboratories, Research Headquarters, Taisho Pharmaceutical Co., Ltd., Saitama, Japan;1. Medicinal Chemistry Berlin, Research & Development, Pharmaceuticals, Bayer AG, D-13353 Berlin, Germany;2. Cross Indication Research, Innovation Campus Berlin, Research & Development, Pharmaceuticals, Bayer AG, D-13353 Berlin, Germany;3. Therapeutic Area Endocrinology, Metabolism and Reproductive Health, Research & Development, Pharmaceuticals, Bayer AG, D-13353 Berlin, Germany;4. Drug Metabolism and Pharmacokinetics, Research & Development, Pharmaceuticals, Bayer AG, D-13353 Berlin, Germany;5. Open Innovation, Research & Development, Pharmaceuticals, Bayer AG, D-13353 Berlin, Germany;1. Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan;2. Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan |
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| 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. |
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| Keywords: | Diabetes Glucose transporter SGLT1 inhibitor SGLT2 inhibitor Bioisostere C-Aryl Glucoside Fluorination |
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