Journal ArticleDOI
Discovery of (S)-6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic acid as a hepatoselective glucokinase activator clinical candidate for treating type 2 diabetes mellitus.
Jeffrey A. Pfefferkorn,Angel Guzman-Perez,John Litchfield,Robert J. Aiello,Judith L. Treadway,John C. Pettersen,Martha L. Minich,Kevin J. Filipski,Christopher S. Jones,Meihua Tu,Gary Erik Aspnes,Hud Lawrence Risley,Jianwei Bian,Benjamin D. Stevens,Patricia Bourassa,Theresa D’Aquila,Levenia Baker,Nicole Barucci,Alan Robertson,Francis Bourbonais,David R. Derksen,Margit MacDougall,Over Cabrera,Jing Chen,Amanda L. Lapworth,James A. Landro,William J. Zavadoski,Karen Atkinson,Nahor Haddish-Berhane,Beijing Tan,Lili Yao,Rachel E. Kosa,Manthena V.S. Varma,Bo Feng,David B. Duignan,Ayman El-Kattan,Sharad B. Murdande,Shenping Liu,Mark Ammirati,John D. Knafels,Paul DaSilva-Jardine,Laurel Sweet,Spiros Liras,Timothy P. Rolph +43 more
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19 is identified as a potent glucokinase activator with a greater than 50-fold liver-to-pancreas ratio of tissue distribution in rodent and non-rodent species, leading to its selection as a clinical development candidate for treating type 2 diabetes.Abstract:
Glucokinase is a key regulator of glucose homeostasis, and small molecule allosteric activators of this enzyme represent a promising opportunity for the treatment of type 2 diabetes. Systemically acting glucokinase activators (liver and pancreas) have been reported to be efficacious but in many cases present hypoglycaemia risk due to activation of the enzyme at low glucose levels in the pancreas, leading to inappropriately excessive insulin secretion. It was therefore postulated that a liver selective activator may offer effective glycemic control with reduced hypoglycemia risk. Herein, we report structure–activity studies on a carboxylic acid containing series of glucokinase activators with preferential activity in hepatocytes versus pancreatic β-cells. These activators were designed to have low passive permeability thereby minimizing distribution into extrahepatic tissues; concurrently, they were also optimized as substrates for active liver uptake via members of the organic anion transporting polypepti...read more
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Targeting hepatic glucose metabolism in the treatment of type 2 diabetes
TL;DR: The molecular mechanisms controlling hepatic gluconeogenesis and glycogen storage are reviewed, and the prospect of therapeutically targeting associated pathways to treat type 2 diabetes is assessed.
Journal ArticleDOI
ChREBP regulates fructose-induced glucose production independently of insulin signaling
Misung Kim,Sarah A. Krawczyk,Ludivine Doridot,Alan J. Fowler,Jennifer X. Wang,Sunia A. Trauger,Hye Lim Noh,Hee Joon Kang,John K. Meissen,Matthew Blatnik,Jason K. Kim,Michelle Lai,Mark A. Herman +12 more
TL;DR: It is found that fructose-induced G6PC activity is a major determinant of hepatic glucose production and reduces hepatic fructose-6-phosphate levels to complete a homeostatic loop and support a carbohydrate-mediated, ChREBP-driven mechanism that contributes to hepatic insulin resistance.
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How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion.
TL;DR: The view that Phospholipid Bilayer diffusion Is Negligible (PBIN) provides a starting hypothesis for assessing cellular drug uptake that is much better supported by the available evidence, and is both more productive and more predictive.
Journal ArticleDOI
Transporter studies in drug development: experience to date and follow-up on decision trees from the International Transporter Consortium.
Donald J. Tweedie,Joseph W. Polli,E Gil Berglund,Huang Sm,Lei Zhang,A Poirier,Xiaoyan Chu,Bo Feng +7 more
TL;DR: The International Transporter Consortium organized a second workshop in March 2012 to expand on the themes developed during the inaugural ITC workshop held in 2008, and focused primarily on the decision trees published from the first workshop.
Journal ArticleDOI
Sulfoximines as Rising Stars in Modern Drug Discovery? Current Status and Perspective on an Emerging Functional Group in Medicinal Chemistry.
Patrick Mäder,Lars Kattner +1 more
TL;DR: Recent developments of sulfoximines are reviewed to demonstrate the scope and limitations of this interesting and versatile functional group in medicinal chemistry and drug discovery.
References
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Journal ArticleDOI
Allosteric Activators of Glucokinase: Potential Role in Diabetes Therapy
Joseph Grimsby,Ramakanth Sarabu,Wendy Lea Corbett,Nancy-Ellen Haynes,Fred Thomas Bizzarro,John W. Coffey,Kevin Richard Guertin,Darryl W. Hilliard,Robert Francis Kester,Paige Erin Mahaney,Linda Marcus,Lida Qi,Cheryl Spence,John Tengi,Mark A. Magnuson,Chang An Chu,Mark T. Dvorozniak,Franz M. Matschinsky,Joseph F. Grippo +18 more
TL;DR: In several rodent models of type 2 diabetes mellitus, GKAs lowered blood glucose levels, improved the results of glucose tolerance tests, and increased hepatic glucose uptake, which may lead to the development of new drug therapies for diabetes.
Journal ArticleDOI
Discovery of 5-[5-fluoro-2-oxo-1,2- dihydroindol-(3Z)-ylidenemethyl]-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase.
Li Sun,Chris Liang,Sheri Shirazian,Yong Zhou,Todd W. Miller,Jean Cui,Juri Y Fukuda,Ji-Yu Chu,Asaad S. Nematalla,Xueyan Wang,Hui Chen,Anand Sistla,Tony C Luu,Flora Tang,James Wei,Cho Tang +15 more
TL;DR: 5-Fluoro-2-oxo-1, 2-dihydroindol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (12b or SU11248) has been found to show the best overall profile in terms of potency for the VEGF-R2 and PDGF-Rbeta tyros
Journal ArticleDOI
Structural basis for allosteric regulation of the monomeric allosteric enzyme human glucokinase
TL;DR: It is demonstrated that global conformational change, including domain reorganization, is induced by glucose binding, which suggests that the positive cooperativity of monomeric glucokinase obeys the "mnemonical mechanism" rather than the well-known concerted model.
Journal ArticleDOI
Assessing the potential of glucokinase activators in diabetes therapy
TL;DR: Several glucokinase activators are now being developed, and have so far been shown to lower blood glucose in several animal models of type 2 diabetes and in initial trials in humans with the disease.
Journal ArticleDOI
The role of alpha-cell dysregulation in fasting and postprandial hyperglycemia in type 2 diabetes and therapeutic implications.
Beth E. Dunning,John E. Gerich +1 more
TL;DR: There is considerable evidence that relative hyperglucagonemia contributes to fasting and postprandial hyperglycemia in patients with T2DM, and there are several new and emerging pharmacotherapies that may improve glycemic control in part by ameliorating the hyperglycemic effects of this relative glucagon excess.
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