title: Design, synthesis, and pharmacological evaluation of N-(4-mono and 4,5-disubstituted thiazol-2-yl)-2-aryl-3-(tetrahydro-2H-pyran-4-yl)propanamides as glucokinase activators.
abstract: A series of N-thiazole substituted arylacetamides were designed on the basis of metabolic mechanism of the aminothiazole fragment as glucokinase (GK) activators for the treatment of type 2 diabetes. Instead of introducing a substituent to block the metabolic sensitive C-5 position on the thiazole core directly, a wide variety of C-4 or both C-4 and C-5 substitutions were explored. Compound R-9k bearing an iso-propyl group as the C-4 substituent was found possessing the highest GK activation potency with an EC(50) of 0.026microM. This compound significantly increased both glucose uptake and glycogen synthesis in rat primary cultured hepatocytes. Moreover, single oral administration of compound R-9k exerted significant reduction of blood glucose levels in both ICR and ob/ob mice. These promising results indicated that compound R-9k is a potent orally active GK activator, and is warranted for further investigation as a new anti-diabetic treatment.
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Fuying
authors.initials: F
authors.lastname: Li
authors.forename: Qingzhang
authors.initials: Q
authors.lastname: Zhu
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ying
authors.initials: Y
authors.lastname: Feng
authors.forename: Ying
authors.initials: Y
authors.lastname: Leng
authors.forename: Ao
authors.initials: A
authors.lastname: Zhang
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005941:Glucokinase / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D006026:Glycoside Hydrolases / Q000187:drug effects; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D051381:Rats; D013844:Thiazoles / Q000737:chemistry
chemical_list: D000081:Acetamides; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D013844:Thiazoles; D005941:Glucokinase; D006026:Glycoside Hydrolases; D005947:Glucose