Discovery of potent and orally active 3-alkoxy-5-phenoxy-N-thiazolyl benzamides as novel allosteric glucokinase activators.

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Iino T, Tsukahara D, Kamata K, Sasaki K, Ohyama S, Hosaka H, Hasegawa T, Chiba M, Nagata Y, Eiki J, Nishimura T

Discovery of potent and orally active 3-alkoxy-5-phenoxy-N-thiazolyl benzamides as novel allosteric glucokinase activators.

Bioorg Med Chem. 2009 Apr 1;17(7):2733-43. doi: 10.1016/j.bmc.2009.02.038. Epub 2009 Feb 25.

PubMed ID

19282189 [ View in PubMed

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Abstract

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.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
2-amino-N-(4-methyl-1,3-thiazol-2-yl)-5-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]benzamide	Glucokinase	EC 50 (nM)	420	N/A	N/A	Details
2-amino-N-(4-methyl-1,3-thiazol-2-yl)-5-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]benzamide	Glucokinase	EC 50 (nM)	140	N/A	N/A	Details