title: 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.
abstract: Novel heteroaryl-containing benzamide derivatives were synthesized and screened using an in vitro assay measuring increases in glucose uptake and glucokinase activity stimulated by 10mM 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 315nM and the induction of a 2.23 fold increase in glucose uptake. Compound 19e exhibited a glucose AUC reduction of 32% (50mg/kg) in an OGTT study with C57BL/6J mice compared to 28% for metformin (300mg/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.
authors.affiliation: Yuhan Research Institute, 25, Tapsil-ro 35beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do, Republic of Korea. Electronic address: kaapjoo@yuhan.co.kr.
authors.forename: Kaapjoo
authors.initials: K
authors.lastname: Park
authors.affiliation: Yuhan Research Institute, 25, Tapsil-ro 35beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do, Republic of Korea.
authors.forename: Byoung Moon
authors.initials: BM
authors.lastname: Lee
authors.affiliation: Yuhan Research Institute, 25, Tapsil-ro 35beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do, Republic of Korea.
authors.forename: Kwan Hoon
authors.initials: KH
authors.lastname: Hyun
authors.affiliation: Yuhan Research Institute, 25, Tapsil-ro 35beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do, Republic of Korea.
authors.forename: Dong Hoon
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Yuhan Research Institute, 25, Tapsil-ro 35beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do, Republic of Korea.
authors.forename: Hyun Ho
authors.initials: HH
authors.lastname: Choi
authors.affiliation: Yuhan Research Institute, 25, Tapsil-ro 35beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do, Republic of Korea.
authors.forename: Hyunmi
authors.initials: H
authors.lastname: Kim
authors.affiliation: Yuhan Research Institute, 25, Tapsil-ro 35beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do, Republic of Korea.
authors.forename: Wonee
authors.initials: W
authors.lastname: Chong
authors.affiliation: Yuhan Research Institute, 25, Tapsil-ro 35beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do, Republic of Korea.
authors.forename: Kyeong Bae
authors.initials: KB
authors.lastname: Kim
authors.affiliation: Yuhan Research Institute, 25, Tapsil-ro 35beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do, Republic of Korea.
authors.forename: Su Youn
authors.initials: SY
authors.lastname: Nam
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D020536:Enzyme Activators / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D005941:Glucokinase / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008820:Mice, Obese; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000593125:3-(4-methanesulfonylphenoxy)-N-(1-(2-methoxyethoxymethyl)-1H-pyrazol-3-yl)-5-(3-methylpyridin-2-yl)benzamide; D001549:Benzamides; D001786:Blood Glucose; D020536:Enzyme Activators; D007004:Hypoglycemic Agents; D007328:Insulin; D013450:Sulfones; D005941:Glucokinase
keywords: Glucokinase activator (GKA); Type 2 diabetes mellitus (T2DM)