Molecular design, synthesis, and hypoglycemic activity of a series of thiazolidine-2,4-diones.
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.
Oguchi
M
M
Medicinal Chemistry Research Laboratories, Sankyo Company, Ltd., 2-58 Hiromachi 1-chome, Shinagawa-ku, Tokyo 140-8710, Japan. oguchi@shina.sankyo.co.jp
Wada
K
K
Honma
H
H
Tanaka
A
A
Kaneko
T
T
Sakakibara
S
S
Ohsumi
J
J
Serizawa
N
N
Fujiwara
T
T
Horikoshi
H
H
Fujita
T
T
D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects; D000818:Animals; D001682:Biological Availability; D002454:Cell Differentiation; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000235:genetics; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006321:Heart / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D008297:Male; D051379:Mice; D009929:Organ Size; D051381:Rats; D000077154:Rosiglitazone; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D045162:Thiazolidinediones
C412819:5-(4-(5-methoxy-3-methyl-3H-imidazo(4,5-b)pyridin-2-ylmethoxy)benzyl)thiazolidine-2,4-dione; D007004:Hypoglycemic Agents; D007093:Imidazoles; D013844:Thiazoles; D045162:Thiazolidinediones; D000077154:Rosiglitazone