Molecular Design, Synthesis, and Hypoglycemic Activity of a Series of Thiazolidine-2,4-diones

• Published in: Journal of medicinal chemistry Vol. 43; no. 16; pp. 3052 - 3066
• Main Authors: Oguchi, Minoru, Wada, Kunio, Honma, Hidehito, Tanaka, Asako, Kaneko, Tomoko, Sakakibara, Sachiko, Ohsumi, Jun, Serizawa, Nobufusa, Fujiwara, Toshihiko, Horikoshi, Hiroyoshi, Fujita, Takashi
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.08.2000; Amer Chemical Soc
• Subjects: 3T3 Cells; Adipocytes - cytology; Adipocytes - drug effects; Animals; Biological and medical sciences; Biological Availability; Cell Differentiation; Chemistry, Medicinal; Diabetes Mellitus - drug therapy; Diabetes Mellitus - genetics; Drug Design; Drug Evaluation, Preclinical; General and cellular metabolism. Vitamins; Heart - drug effects; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - toxicity; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; Imidazoles - toxicity; Life Sciences & Biomedicine; Male; Medical sciences; Mice; Organ Size; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Rats; Rosiglitazone; Science & Technology; Structure-Activity Relationship; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacology; Thiazoles - toxicity; Thiazolidinediones; ACTIVATED RECEPTOR-GAMMA; HUMAN-DISEASE; INSULIN-RESISTANCE; GLUCOSE; CIGLITAZONE; THIAZOLIDINEDIONES; EXPRESSION; ANTIDIABETIC AGENT; ADIPOSE-TISSUE; NIDDM; Endocrinopathy; Adipocyte; Rat; Nitrogen heterocycle; Thiazole derivatives; Hypoglycemic agent; Structure activity relation; Hydrochlorides; Bicyclic compound; Aromatic compound; Chemical synthesis; Sulfur nitrogen heterocycle; Diabetes mellitus; Rodentia; Oral administration; Bioavailability; In vitro; In vivo; Vertebrata; Chemotherapy; Experimental disease; Mammalia; Treatment; Mouse; Animal; Rosiglitazone
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm990522t

A series of imidazopyridine thiazolidine-2,4-diones were designed and synthesized from their corresponding pyridines. These compounds represent conformationally restricted analogues of the novel hypoglycemic compound rosiglitazone (5). The series was evaluated for its effect on insulin-induced 3T3-L1 adipocyte differentiation in vitro and its hypoglycemic activity in the genetically diabetic KK mouse in vivo. The structure−activity relationships are discussed. On the basis of the in vivo potency, 5-[4-(5-methoxy-3-methyl-3H-imidazo[4,5-b]pyridin-2-ylmethoxy)benzyl]thiazolidine-2,4-dione (19a) was selected as the candidate for further studies in a clinical setting.