کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10583746 | 981305 | 2014 | 14 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Discovery of 3-(4-methanesulfonylphenoxy)-N-[1-(2-methoxy-ethoxymethyl)-1H-pyrazol-3-yl]-5-(3-methylpyridin-2-yl)-benzamide as a novel glucokinase activator (GKA) for the treatment of type 2 diabetes mellitus
دانلود مقاله + سفارش ترجمه
دانلود مقاله ISI انگلیسی
رایگان برای ایرانیان
کلمات کلیدی
TZDsodium-glucose co-transporter 2GSISSGLT2DPP-4T2DMOGTTGKAOral glucose tolerance test - آزمون تحمل گلوکز خوراکیGlucose-stimulated insulin secretion - ترشح انسولین تحریک شده توسط گلوکزThiazolidinedione - تیازولیدیدئونtype 2 diabetes mellitus (T2DM) - دیابت نوع 2 (T2DM)Type 2 diabetes mellitus - دیابت نوع دوDipeptidyl peptidase-4 - دیپپتیدیل پپتیداز 4Sulfonylurea - سولفونیل اورهPharmacokinetics - فارماکوکینتیکGlucokinase activator - فعال کننده گلوکوکینازGlucokinase - گلوکوکیناز
موضوعات مرتبط
مهندسی و علوم پایه
شیمی
شیمی آلی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Novel heteroaryl-containing benzamide derivatives were synthesized and screened using an in vitro assay measuring increases in glucose uptake and glucokinase activity stimulated by 10Â mM glucose in rat hepatocytes. From a library of synthesized compounds, 3-(4-methanesulfonylphenoxy)-N-[1-(2-methoxy-ethoxymethyl)-1H-pyrazol-3-yl]-5-(3-methyl pyridin-2-yl)-benzamide (19e) was identified as a potent glucokinase activator with assays demonstrating an EC50 of 315Â nM and the induction of a 2.23 fold increase in glucose uptake. Compound 19e exhibited a glucose AUC reduction of 32% (50Â mg/kg) in an OGTT study with C57BL/6J mice compared to 28% for metformin (300Â mg/kg). Single treatment of the compound in C57BL/J6 and ob/ob mice elicited basal glucose lowering activity, while in a two-week repeated dose study with ob/ob mice, the compound significantly decreased blood glucose levels with no evidence of hypoglycemia risk. In addition, 19e exhibited favorable pharmacokinetic parameters in mice and rats and excellent safety margins in liver and testicular toxicity studies. Compound 19e was therefore selected as a development candidate for the potential treatment of type 2 diabetes.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry - Volume 22, Issue 7, 1 April 2014, Pages 2280-2293
Journal: Bioorganic & Medicinal Chemistry - Volume 22, Issue 7, 1 April 2014, Pages 2280-2293
نویسندگان
Kaapjoo Park, Byoung Moon Lee, Kwan Hoon Hyun, Dong Hoon Lee, Hyun Ho Choi, Hyunmi Kim, Wonee Chong, Kyeong Bae Kim, Su Youn Nam,