Discovery of potent and orally active 3-alkoxy-5-phenoxy-N-thiazolyl benzamides as novel allosteric glucokinase activators.
Identification and synthesis of novel 3-alkoxy-5-phenoxy-N-thiazolyl benzamides as glucokinase activators are described. Removal of an aniline structure of the prototype lead (2a) and incorporation of an alkoxy or phenoxy substituent led to the identification of 3-Isopropoxy-5-[4-(methylsulfonyl)phenoxy]-N-(4-methyl-1,3-thiazol-2-yl)benzamide (27e) as a novel, potent, and orally bioavailable GK activator. Rat oral glucose tolerance test indicated that 27e exhibited a glucose-lowering effect after 10 mg/kg oral administration.
Iino
Tomoharu
T
Banyu Tsukuba Research Institute, Banyu Pharmaceutical Co. Ltd, Okubo 3, Tsukuba 300-2611, Ibaraki, Japan. tomoharu_iino@merck.com
Tsukahara
Daisuke
D
Kamata
Kenji
K
Sasaki
Kaori
K
Ohyama
Sumika
S
Hosaka
Hideka
H
Hasegawa
Takuro
T
Chiba
Masato
M
Nagata
Yasufumi
Y
Eiki
Jun-ichi
J
Nishimura
Teruyuki
T
D000284:Administration, Oral; D000494:Allosteric Regulation; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D055808:Drug Discovery; D005941:Glucokinase / Q000737:chemistry* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
C541070:3-isopropoxy-5-(4-(methylsulfonyl)phenoxy)-N-(4-methyl-1,3-thiazol-2-yl)benzamide; D001549:Benzamides; D007004:Hypoglycemic Agents; D005941:Glucokinase; D005947:Glucose