Literature summary for 2.7.1.1 extracted from

Wang, Z.; Shi, X.; Zhang, H.; Yu, L.; Cheng, Y.; Zhang, H.; Zhang, H.; Zhou, J.; Chen, J.; Shen, X.; Duan, W.
Discovery of cycloalkyl-fused N-thiazol-2-yl-benzamides as tissue non-specific glucokinase activators Design, synthesis, and biological evaluation (2017), Eur. J. Med. Chem., 139, 128-152 .

Activating Compound

Activating Compound	Comment	Organism
2-(3-[4-(azetidine-1-carbonyl)phenoxy]-5-[[(2S)-1-methoxypropan-2-yl]oxy]benzamido)-N,N-dimethyl-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxamide	maximal activation: 2.35fold	Homo sapiens
3-[4-(azetidine-1-carbonyl)phenoxy]-5-[[(2S)-1-methoxypropan-2-yl]oxy]-N-(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)benzamide	maximal activation: 2.2fold	Homo sapiens
3-[4-(azetidine-1-carbonyl)phenoxy]-5-[[(2S)-1-methoxypropan-2-yl]oxy]-N-[5-(2-oxo-1,2-dihydropyridin-4-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl]benzamide	maximal activation: 2.13fold	Homo sapiens
3-[4-(azetidine-1-carbonyl)phenoxy]-5-[[(2S)-1-methoxypropan-2-yl]oxy]-N-[5-(pyridin-2-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl]benzamide	maximal activation: 1.92fold	Homo sapiens
3-[4-(azetidine-1-carbonyl)phenoxy]-5-[[(2S)-1-methoxypropan-2-yl]oxy]-N-[5-(pyrimidin-2-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl]benzamide	maximal activation: 2.35fold	Homo sapiens
3-[4-(azetidine-1-carbonyl)phenoxy]-5-[[(2S)-1-methoxypropan-2-yl]oxy]-N-[5-(pyrimidin-4-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl]benzamide	maximal activation: 2.53fold	Homo sapiens
3-[4-(azetidine-1-carbonyl)phenoxy]-N-[5-(2-hydroxyethyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl]-5-[[(2S)-1-methoxypropan-2-yl]oxy]benzamide	maximal activation: 1.97fold	Homo sapiens
3-[4-(azetidine-1-carbonyl)phenoxy]-N-[5-(2-methoxyethyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl]-5-[[(2S)-1-methoxypropan-2-yl]oxy]benzamide	maximal activation: 1.76fold	Homo sapiens
3-[4-(methanesulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]-N-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)benzamide	maximal activation: 3.42fold	Homo sapiens
3-[4-(methanesulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]-N-(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)benzamide	maximal activation: 3.41fold	Homo sapiens
3-[4-(methanesulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]-N-(5-phenyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)benzamide	maximal activation: 2.05fold	Homo sapiens
3-[4-(methanesulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]-N-(7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)benzamide	maximal activation: 2.61fold	Homo sapiens
3-[4-(methanesulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]-N-[5-(propan-2-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl]benzamide	maximal activation: 2fold	Homo sapiens
3-[4-(methanesulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]-N-[5-(pyridin-2-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl]benzamide	maximal activation: 2.39fold	Homo sapiens
3-[4-(methanesulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]-N-[5-(pyridin-3-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl]benzamide	maximal activation: 2.7fold	Homo sapiens
3-[4-(methanesulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]-N-[5-(pyridin-4-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl]benzamide	maximal activation: 2.97fold	Homo sapiens
ethyl 2-(3-[4-(azetidine-1-carbonyl)phenoxy]-5-[[(2S)-1-methoxypropan-2-yl]oxy]benzamido)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate	maximal activation: 2.22fold	Homo sapiens
methyl 2-(3-[4-(azetidine-1-carbonyl)phenoxy]-5-[[(2S)-1-methoxypropan-2-yl]oxy]benzamido)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate	maximal activation: 2.38fold	Homo sapiens
N-(5,6-dihydro-4H-cyclopenta[d][1,3]thiazol-2-yl)-3-[4-(methanesulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]benzamide	maximal activation: 4.8fold	Homo sapiens
N-(5-acetyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)-3-[4-(methanesulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]benzamide	maximal activation: 2.5fold	Homo sapiens
N-(5-benzyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)-3-[4-(methanesulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]benzamide	maximal activation: 2.1fold	Homo sapiens
N-(5-ethyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)-3-[4-(methanesulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]benzamide	maximal activation: 2.08fold	Homo sapiens
N-(6,7-dihydro-4H-pyrano[4,3-d][1,3]thiazol-2-yl)-3-[4-(methanesulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]benzamide	maximal activation: 2.17fold	Homo sapiens
PF-04937319	maximal activation: 2.11fold	Homo sapiens
tert-butyl (S)-2-(3-(4-(azetidine-1-carbonyl)phenoxy)-5-((1-methoxypropan-2-yl)oxy)benzamido)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate	glucokinase activators are being developed for the treatment of type 2 diabetes mellitus. Glucokinase activators have risks of hypoglycemia caused by over-activation of glucokinase in islet cells and dyslipidemia caused by over-activation of intrahepatic glucokinase. In the effort to mitigate risks of hypoglycemia and dyslipidemia while maintaining the promising efficacy of glucokinase activator. tert-Butyl (S)-2-(3-(4-(azetidine-1-carbonyl)phenoxy)-5-((1-methoxypropan-2-yl)oxy)benzamido)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate shows a good balance between in vitro potency and enzyme kinetic parameters, and protects beta-cells from streptozotocin-induced apoptosis. Chronic treatment of this compound demonstrates its potent activity in regulation of glucose homeostasis and low risk of dyslipidemia with diabetic db/db mice in oral glucose tolerance test. Acute treatment of this compound does not induce hypoglycemia in C57BL/6J mice even at 200 mg/kg via oral administration	Homo sapiens
tert-butyl 2-(3-[4-(azetidine-1-carbonyl)-3-fluorophenoxy]-5-[[(2S)-1-methoxypropan-2-yl]oxy]benzamido)-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate	maximal activation: 2.83 fold	Homo sapiens
tert-butyl 2-(3-[4-(azetidine-1-carbonyl)phenoxy]-5-[[(2R)-1-methoxypropan-2-yl]oxy]benzamido)-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate	maximal activation: 2.96fold	Homo sapiens
tert-butyl 2-(3-[4-(azetidine-1-carbonyl)phenoxy]-5-[[(2S)-1-hydroxypropan-2-yl]oxy]benzamido)-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate	maximal activation: 2.62fold	Homo sapiens
tert-butyl 2-(3-[4-(azetidine-1-carbonyl)phenoxy]-5-[[(2S)-1-methoxypropan-2-yl]oxy]benzamido)-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate	maximal activation: 2.65fold	Homo sapiens
tert-butyl 2-(3-[4-(azetidine-1-carbonyl)phenoxy]-5-[[(2S)-1-methoxypropan-2-yl]oxy]benzamido)-6,7-dihydro[1,3]thiazolo[5,4-b]pyridine-4(5H)-carboxylate	maximal activation: 1.8fold	Homo sapiens
tert-butyl 2-(3-[4-(azetidine-1-carbonyl)phenoxy]-5-[[(2S)-1-methoxypropan-2-yl]oxy]benzamido)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate	maximal activation: 2.84fold	Homo sapiens
tert-butyl 2-(3-[[6-(azetidine-1-carbonyl)pyridin-3-yl]oxy]-5-[(1-methoxypropan-2-yl)oxy]benzamido)-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate	maximal activation: 2.1fold	Homo sapiens
tert-butyl 2-(3-[[6-(methanesulfonyl)pyridin-3-yl]oxy]-5-[(1-methoxypropan-2-yl)oxy]benzamido)-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate	maximal activation: 4.07fold	Homo sapiens
tert-butyl 2-[3-(3,5-difluorophenoxy)-5-[[(2S)-1-methoxypropan-2-yl]oxy]benzamido]-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate	maximal activation: 2.72fold	Homo sapiens
tert-butyl 2-[3-(benzyloxy)-5-[4-(methanesulfonyl)phenoxy]benzamido]-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate	maximal activation: 2.3fold	Homo sapiens
tert-butyl 2-[3-(cyclohexyloxy)-5-[4-(methanesulfonyl)phenoxy]benzamido]-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate	maximal activation: 1.71fold	Homo sapiens
tert-butyl 2-[3-(cyclopentylmethoxy)-5-[4-(methanesulfonyl)phenoxy]benzamido]-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate	maximal activation: 2.11fold	Homo sapiens
tert-butyl 2-[3-(cyclopentyloxy)-5-[4-(methanesulfonyl)phenoxy]benzamido]-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate	maximal activation: 3.17fold	Homo sapiens
tert-butyl 2-[3-[2-(methanesulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]benzamido]-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate	maximal activation: 1.89fold	Homo sapiens
tert-butyl 2-[3-[3-(methanesulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]benzamido]-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate	maximal activation: 2.74fold	Homo sapiens
tert-butyl 2-[3-[4-(azetidine-1-carbonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]benzamido]-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate	maximal activation: 2.89fold	Homo sapiens
tert-butyl 2-[3-[4-(azetidine-1-sulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]benzamido]-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate	maximal activation: 3.26fold	Homo sapiens
tert-butyl 2-[3-[4-(cyclopropanesulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]benzamido]-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate	maximal activation: 3.12fold	Homo sapiens
tert-butyl 2-[3-[4-(dimethylcarbamoyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]benzamido]-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate	maximal activation: 1.91fold	Homo sapiens
tert-butyl 2-[3-[4-(ethanesulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]benzamido]-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate	maximal activation: 2.37fold	Homo sapiens
tert-butyl 2-[3-[4-(methanesulfonyl)phenoxy]-5-(2-methoxyethoxy)benzamido]-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate	maximal activation: 2.3fold	Homo sapiens
tert-butyl 2-[3-[4-(methanesulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]benzamido]-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate	maximal activation: 2.94fold	Homo sapiens
tert-butyl 2-[3-[4-(methanesulfonyl)phenoxy]-5-[(propan-2-yl)oxy]benzamido]-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate	maximal activation: 3.55fold	Homo sapiens

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	-	-	-

Source Tissue

Source Tissue	Comment	Organism	Textmining
pancreatic beta cell	-	Homo sapiens	-

General Information

General Information	Comment	Organism
drug target	glucokinase activators are being developed for the treatment of type 2 diabetes mellitus. Glucokinase activators have risks of hypoglycemia caused by over-activation of glucokinase in islet cells and dyslipidemia caused by over-activation of intrahepatic glucokinase. In the effort to mitigate risks of hypoglycemia and dyslipidemia while maintaining the promising efficacy of glucokinase activator. tert-Butyl (S)-2-(3-(4-(azetidine-1-carbonyl)phenoxy)-5-((1-methoxypropan-2-yl)oxy)benzamido)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate shows a good balance between in vitro potency and enzyme kinetic parameters, and protects beta-cells from streptozotocin-induced apoptosis. Chronic treatment of this compound demonstrates its potent activity in regulation of glucose homeostasis and low risk of dyslipidemia with diabetic db/db mice in oral glucose tolerance test. Acute treatment of this compound does not induce hypoglycemia in C57BL/6J mice even at 200 mg/kg via oral administration	Homo sapiens