共查询到20条相似文献,搜索用时 15 毫秒
1.
Sinz C Chang J Lins AR Brady E Candelore M Dallas-Yang Q Ding V Jiang G Lin Z Mock S Qureshi S Salituro G Saperstein R Shang J Szalkowski D Tota L Vincent S Wright M Xu S Yang X Zhang B Tata J Kim R Parmee E 《Bioorganic & medicinal chemistry letters》2011,21(23):7131-7136
In the course of the development of an aminobenzimidazole class of human glucagon receptor (hGCGR) antagonists, a novel class of cyclic guanidine hGCGR antagonists was discovered. Rapid N-dealkylation resulted in poor pharmacokinetic profiles for the benchmark compound in this series. A strategy aimed at blocking oxidative dealkylation led to a series of compounds with improved rodent pharmacokinetic profiles. One compound was orally efficacious in a murine glucagon challenge pharmacodynamic model and also significantly lowered glucose levels in a murine diabetes model. 相似文献
2.
James Mu Sajjad A. Qureshi Edward J. Brady Eric S. Muise Mari Rios Candelore Guoqiang Jiang Zhihua Li Margaret S. Wu Xiaodong Yang Qing Dallas-Yang Corey Miller Yusheng Xiong Ronald B. Langdon Emma R. Parmee Bei B. Zhang 《PloS one》2012,7(11)
Hyperglucagonemia is implicated in the pathophysiology of hyperglycemia. Antagonism of the glucagon receptor (GCGR) thus represents a potential approach to diabetes treatment. Herein we report the characterization of GRA1, a novel small-molecule GCGR antagonist that blocks glucagon binding to the human GCGR (hGCGR) and antagonizes glucagon-induced intracellular accumulation of cAMP with nanomolar potency. GRA1 inhibited glycogenolysis dose-dependently in primary human hepatocytes and in perfused liver from hGCGR mice, a transgenic line of mouse that expresses the hGCGR instead of the murine GCGR. When administered orally to hGCGR mice and rhesus monkeys, GRA1 blocked hyperglycemic responses to exogenous glucagon. In several murine models of diabetes, acute and chronic dosing with GRA1 significantly reduced blood glucose concentrations and moderately increased plasma glucagon and glucagon-like peptide-1. Combination of GRA1 with a dipeptidyl peptidase-4 inhibitor had an additive antihyperglycemic effect in diabetic mice. Hepatic gene-expression profiling in monkeys treated with GRA1 revealed down-regulation of numerous genes involved in amino acid catabolism, an effect that was paralleled by increased amino acid levels in the circulation. In summary, GRA1 is a potent glucagon receptor antagonist with strong antihyperglycemic efficacy in preclinical models and prominent effects on hepatic gene-expression related to amino acid metabolism. 相似文献
3.
Kim RM Chang J Lins AR Brady E Candelore MR Dallas-Yang Q Ding V Dragovic J Iliff S Jiang G Mock S Qureshi S Saperstein R Szalkowski D Tamvakopoulos C Tota L Wright M Yang X Tata JR Chapman K Zhang BB Parmee ER 《Bioorganic & medicinal chemistry letters》2008,18(13):3701-3705
The discovery and optimization of potent and selective aminobenzimidazole glucagon receptor antagonists are described. One compound possessing moderate pharmacokinetic properties in multiple preclinical species was orally efficacious at inhibiting glucagon-mediated glucose excursion in transgenic mice expressing the human glucagon receptor, and in rhesus monkeys. The compound also significantly lowered glucose levels in a murine model of diabetes. 相似文献
4.
Discovery of novel, potent, and orally active spiro-urea human glucagon receptor antagonists 总被引:4,自引:0,他引:4
Shen DM Zhang F Brady EJ Candelore MR Dallas-Yang Q Ding VD Dragovic J Feeney WP Jiang G McCann PE Mock S Qureshi SA Saperstein R Shen X Tamvakopoulos C Tong X Tota LM Wright MJ Yang X Zheng S Chapman KT Zhang BB Tata JR Parmee ER 《Bioorganic & medicinal chemistry letters》2005,15(20):4564-4569
A novel class of spiro-ureas has been discovered as potent human glucagon receptor antagonists in both binding and functional assays. Preliminary studies have revealed that compound 15 is an orally active human glucagon receptor antagonist in a transgenic murine pharmacodynamic model at 10 and 30 mpk. Compound 15 is orally bioavailable in several preclinical species and shows selectivity toward cardiac ion channels and other family B receptors, such as hGIP1 and hGLP. 相似文献
5.
Mihalic JT Chen X Fan P Chen X Fu Y Liang L Reed M Tang L Chen JL Jaen J Li L Dai K 《Bioorganic & medicinal chemistry letters》2011,21(23):7001-7005
A new class of MCHR1 antagonists was discovered via a high-throughput screen. Optimization of the lead structure resulted in the identification of indole 10e. This compound possesses good pharmacokinetic properties across preclinical species and is efficacious in reducing food consumption in an MCH cannulated rat model and a cynomolgus monkey food consumption model. 相似文献
6.
Discovery and investigation of a novel class of thiophene-derived antagonists of the human glucagon receptor 总被引:1,自引:0,他引:1
Duffy JL Kirk BA Konteatis Z Campbell EL Liang R Brady EJ Candelore MR Ding VD Jiang G Liu F Qureshi SA Saperstein R Szalkowski D Tong S Tota LM Xie D Yang X Zafian P Zheng S Chapman KT Zhang BB Tata JR 《Bioorganic & medicinal chemistry letters》2005,15(5):1401-1405
A novel class of antagonists of the human glucagon receptor (hGCGR) has been discovered. Systematic modification of the lead compound identified substituents that were essential for activity and those that were amenable to further optimization. This SAR exploration resulted in the synthesis of 13, which exhibited good potency as an hGCGR functional antagonist (IC50 = 34 nM) and moderate bioavailability (36% in mice). 相似文献
7.
Globular adiponectin protected ob/ob mice from diabetes and ApoE-deficient mice from atherosclerosis 总被引:84,自引:0,他引:84
Yamauchi T Kamon J Waki H Imai Y Shimozawa N Hioki K Uchida S Ito Y Takakuwa K Matsui J Takata M Eto K Terauchi Y Komeda K Tsunoda M Murakami K Ohnishi Y Naitoh T Yamamura K Ueyama Y Froguel P Kimura S Nagai R Kadowaki T 《The Journal of biological chemistry》2003,278(4):2461-2468
The adipocyte-derived hormone adiponectin has been shown to play important roles in the regulation of energy homeostasis and insulin sensitivity. In this study, we analyzed globular domain adiponectin (gAd) transgenic (Tg) mice crossed with leptin-deficient ob/ob or apoE-deficient mice. Interestingly, despite an unexpected similar body weight, gAd Tg ob/ob mice showed amelioration of insulin resistance and beta-cell degranulation as well as diabetes, indicating that globular adiponectin and leptin appeared to have both distinct and overlapping functions. Amelioration of diabetes and insulin resistance was associated with increased expression of molecules involved in fatty acid oxidation such as acyl-CoA oxidase, and molecules involved in energy dissipation such as uncoupling proteins 2 and 3 and increased fatty acid oxidation in skeletal muscle of gAd Tg ob/ob mice. Moreover, despite similar plasma glucose and lipid levels on an apoE-deficient background, gAd Tg apoE-deficient mice showed amelioration of atherosclerosis, which was associated with decreased expression of class A scavenger receptor and tumor necrosis factor alpha. This is the first demonstration that globular adiponectin can protect against atherosclerosis in vivo. In conclusion, replenishment of globular adiponectin may provide a novel treatment modality for both type 2 diabetes and atherosclerosis. 相似文献
8.
Shen DM Brady EJ Candelore MR Dallas-Yang Q Ding VD Feeney WP Jiang G McCann ME Mock S Qureshi SA Saperstein R Shen X Tong X Tota LM Wright MJ Yang X Zheng S Chapman KT Zhang BB Tata JR Parmee ER 《Bioorganic & medicinal chemistry letters》2011,21(1):76-81
A novel class of 1,3,5-pyrazoles has been discovered as potent human glucagon receptor antagonists. Notably, compound 26 is orally bioavailable in several preclinical species and shows selectivity towards cardiac ion channels, other family B receptors such hGIP and hGLP1, and a large panel of enzymes and additional receptors. When dosed orally, compound 26 is efficacious in suppressing glucagon induced plasma glucose excursion in rhesus monkey and transgenic murine pharmacodynamic models at 1 and 10 mpk, respectively. 相似文献
9.
Mengxi Jiang Jinhan He Heidi Kucera Nilesh W. Gaikwad Bin Zhang Meishu Xu Robert M. O'Doherty Kyle W. Selcer Wen Xie 《The Journal of biological chemistry》2014,289(12):8086-8097
The steroid sulfatase (STS)-mediated desulfation is a critical metabolic mechanism that regulates the chemical and functional homeostasis of endogenous and exogenous molecules. In this report, we first showed that the liver expression of Sts was induced in both the high fat diet (HFD) and ob/ob models of obesity and type 2 diabetes and during the fed to fasting transition. In defining the functional relevance of STS induction in metabolic disease, we showed that overexpression of STS in the liver of transgenic mice alleviated HFD and ob/ob models of obesity and type 2 diabetes, including reduced body weight, improved insulin sensitivity, and decreased hepatic steatosis and inflammation. Interestingly, STS exerted its metabolic benefit through sex-specific mechanisms. In female mice, STS may have increased hepatic estrogen activity by converting biologically inactive estrogen sulfates to active estrogens and consequently improved the metabolic functions, whereas ovariectomy abolished this protective effect. In contrast, the metabolic benefit of STS in males may have been accounted for by the male-specific decrease of inflammation in white adipose tissue and skeletal muscle as well as a pattern of skeletal muscle gene expression that favors energy expenditure. The metabolic benefit in male STS transgenic mice was retained after castration. Treatment with the STS substrate estrone sulfate also improved metabolic functions in both the HFD and ob/ob models. Our results have uncovered a novel function of STS in energy metabolism and type 2 diabetes. Liver-specific STS induction or estrogen/estrogen sulfate delivery may represent a novel approach to manage metabolic syndrome. 相似文献
10.
Human DQ8 can substitute for murine I-Ag7 in the selection of diabetogenic T cells restricted to I-Ag7 总被引:1,自引:0,他引:1
The strong association of type 1 diabetes with specific MHC class II genes, such as I-A(g7) in nonobese diabetic mice and HLA-DQ8 in humans, suggests that MHC class II molecules play an important role in the development of the disease. To test whether human DQ8 molecules could cross the species barrier and functionally replace their murine homolog I-A(g7), we generated DQ8/BDC2.5 transgenic mice. We have shown that BDC2.5 transgenic T cells are selected on DQ8 in the thymus and cause diabetes in a manner similar to that seen when the T cells are selected on H2(g7). Splenocytes from DQ8/BDC2.5 mice also showed reactivity toward islets in vitro as seen in H-2(g7)/BDC2.5 mice. We conclude that DQ8 molecules not only share structural similarity with the murine homolog I-A(g7), but also can cross the species barrier and functionally replace I-A(g7) molecules to stimulate diabetogenic T cells and produce diabetes. 相似文献
11.
Hall A Billinton A Brown SH Chowdhury A Giblin GM Goldsmith P Hurst DN Naylor A Patel S Scoccitti T Theobald PJ 《Bioorganic & medicinal chemistry letters》2008,18(8):2684-2690
We describe the medicinal chemistry approach that generated a novel indole series of EP(1) receptor antagonists. The SAR of this new template was evaluated and culminated in the identification of compound 12g which demonstrated in vivo efficacy in a preclinical model of inflammatory pain. 相似文献
12.
Impaired Coronary and Renal Vascular Function in Spontaneously Type 2 Diabetic Leptin-Deficient Mice
Helena U. Westergren Julia Gr?nros Suvi E. Heinonen Tasso Miliotis Karin Jennbacken Alan Sabirsh Anette Ericsson Ann-Cathrine J?nsson-Rylander Sara Svedlund Li-Ming Gan 《PloS one》2015,10(6)
Background
Type 2 diabetes is associated with macro- and microvascular complications in man. Microvascular dysfunction affects both cardiac and renal function and is now recognized as a main driver of cardiovascular mortality and morbidity. However, progression of microvascular dysfunction in experimental models is often obscured by macrovascular pathology and consequently demanding to study. The obese type 2 diabetic leptin-deficient (ob/ob) mouse lacks macrovascular complications, i.e. occlusive atherosclerotic disease, and may therefore be a potential model for microvascular dysfunction. The present study aimed to test the hypothesis that these mice with an insulin resistant phenotype might display microvascular dysfunction in both coronary and renal vascular beds.Methods and Results
In this study we used non-invasive Doppler ultrasound imaging to characterize microvascular dysfunction during the progression of diabetes in ob/ob mice. Impaired coronary flow velocity reserve was observed in the ob/ob mice at 16 and 21 weeks of age compared to lean controls. In addition, renal resistivity index as well as pulsatility index was higher in the ob/ob mice at 21 weeks compared to lean controls. Moreover, plasma L-arginine was lower in ob/ob mice, while asymmetric dimethylarginine was unaltered. Furthermore, a decrease in renal vascular density was observed in the ob/ob mice.Conclusion
In parallel to previously described metabolic disturbances, the leptin-deficient ob/ob mice also display cardiac and renal microvascular dysfunction. This model may therefore be suitable for translational, mechanistic and interventional studies to improve the understanding of microvascular complications in type 2 diabetes. 相似文献13.
Tomomichi Chonan Hiroaki Tanaka Daisuke Yamamoto Miyoko Yashiro Takahiro Oi Daisuke Wakasugi Ayumi Ohoka-Sugita Fusayo Io Hiroko Koretsune Akira Hiratate 《Bioorganic & medicinal chemistry letters》2010,20(13):3965-3968
Acetyl-CoA carboxylases (ACCs), the rate limiting enzymes in de novo lipid synthesis, play important roles in modulating energy metabolism. The inhibition of ACC has demonstrated promising therapeutic potential for treating obesity and type 2 diabetes mellitus in transgenic mice and preclinical animal models. We describe herein the structure-based design and synthesis of a novel series of disubstituted (4-piperidinyl)-piperazine derivatives as ACC inhibitors. Our structure-based approach led to the discovery of the indole derivatives 13i and 13j, which exhibited potent in vitro ACC inhibitory activity. 相似文献
14.
Preclinical study of the long-range safety and anti-inflammatory effects of high-dose oral meglumine
Kaylend Manley Arturo Bravo-Nuevo Allyson R. Minton Summer Sedano Alice Marcy Melvin Reichman Annette Tobia Carol M. Artlett Susan K. Gilmour Lisa D. Laury-Kleintop George C. Prendergast 《Journal of cellular biochemistry》2019,120(7):12051-12062
Meglumine is a methylamino derivative of sorbitol that is an approved drug excipient. Recent preclinical studies suggest that administration of high-dose oral meglumine can exert beneficial medicinal effects to treat diabetes, obesity, and fatty liver disease (NAFLD/nonalcoholic steatohepatitis [NASH]). Here we address gaps in knowledge about the pharmacology and toxicology of this substance administered at high concentrations to explore its medicinal potential. We observed that high-dose meglumine limited secretion of proinflammatory cytokines and cell adhesion molecules from activated human THP-1 or murine RAW264.7 monocytes. Preclinical pharmacokinetic analysis in Swiss mice confirmed that meglumine was orally available. Informed by this data, oral doses of 18 to 75 mM meglumine were administered ad libitum in the drinking water of Sprague-Dawley rats and two cohorts of C57BL/6 mice housed in different vivariums. In a 32-week study, urinary isoprostane levels trended lower in subjects consistent with the possibility of anti-inflammatory effects. In full lifespan studies, there was no detrimental effect on longevity. Heart function evaluated in C57BL/6 mice using an established noninvasive cardiac imaging system showed no detrimental effects on ejection fraction, fractional shortening, left ventricle function or volume, and cardiac output in mice up to 15-month old, with a potential positive trend in heart function noted in elderly mice consistent with earlier reported benefits on muscle stamina. Finally, in a transgenic model of inflammation-associated skin carcinogenesis, the incidence, number, and growth of skin tumors trended lower in subjects receiving meglumine. Overall, the evidence obtained illustrating the long-range safety of high-dose oral meglumine support the rationale for its evaluation as a low-cost modality to limit diabetes, hypertriglyceridemia, and NAFLD/NASH. 相似文献
15.
Andrews MD Fish PV Blagg J Brabham TK Brennan PE Bridgeland A Brown AD Bungay PJ Conlon KM Edmunds NJ af Forselles K Gibbons CP Green MP Hanton G Holbrook M Jessiman AS McIntosh K McMurray G Nichols CL Root JA Storer RI Sutton MR Ward RV Westbrook D Whitlock GA 《Bioorganic & medicinal chemistry letters》2011,21(9):2715-2720
New pyrimido[4,5-d]azepines 7 are disclosed as potent 5-HT2C receptor agonists. A preferred example, 7b had minimal activation at either the 5-HT2A or 5-HT2B receptors combined with robust efficacy in a preclinical canine model of stress urinary incontinence (SUI) and attractive pharmacokinetic and safety properties. Based on this profile, 7b (PF-3246799) was identified as a candidate for clinical development for the treatment of SUI. In addition, it proved to be critical to build an understanding of the translation between recombinant cell-based systems, native tissue preparations and in vivo preclinical models. This was a significant undertaking and proved to be crucial in compound selection. 相似文献
16.
Severe hypercholesterolemia, hypertriglyceridemia, and atherosclerosis in mice lacking both leptin and the low density lipoprotein receptor. 总被引:15,自引:0,他引:15
A H Hasty H Shimano J Osuga I Namatame A Takahashi N Yahagi S Perrey Y Iizuka Y Tamura M Amemiya-Kudo T Yoshikawa H Okazaki K Ohashi K Harada T Matsuzaka H Sone T Gotoda R Nagai S Ishibashi N Yamada 《The Journal of biological chemistry》2001,276(40):37402-37408
Leptin-deficient mice (ob/ob) are an excellent murine model for obesity, insulin resistance, and diabetes, all of which are components of a multiple risk factor syndrome that, along with hypercholesterolemia, precipitates a potential high risk for atherosclerosis. In the current study, we show an unexpectedly severe hyperlipidemia in ob/ob mice on a background of low density lipoprotein receptor (LDLR) deficiency (-/-). Doubly mutant mice (LDLR-/-;ob/ob) exhibited striking elevations in both total plasma cholesterol (TC) and triglyceride (TG) levels (1715 +/- 87 and 1016 +/- 172 mg/dl, respectively), at age 3-4 months, resulting in extensive atherosclerotic lesions throughout the aorta by 6 months. Lipoprotein analyses revealed the elevated TC and TG levels to be due to a large increase in an apoB-containing broad-beta remnant lipoprotein fraction. While fasting, diet restriction, and low level leptin treatment significantly lowered TG levels, they caused only slight changes in TC levels. Hepatic cholesterol and triglyceride contents as well as mRNA levels of cholesterologenic and lipogenic enzymes suggest that leptin deficiency increased hepatic triglyceride production but did not change cholesterol production in ob/ob mice regardless of their LDLR genotype. These data provide evidence that the hypertriglyceridemia and hypercholesterolemia in the doubly mutant mice are caused by distinct mechanisms and point to the possibility that leptin might have some impact on plasma cholesterol metabolism, possibly through an LDLR-independent pathway. This model will be an excellent tool for future studies on the relationship between impaired fuel metabolism, increased plasma remnant lipoproteins, diabetes, and atherosclerosis. 相似文献
17.
Havari E Lennon-Dumenil AM Klein L Neely D Taylor JA McInerney MF Wucherpfennig KW Lipes MA 《Journal of immunology (Baltimore, Md. : 1950)》2004,173(2):787-796
Although HLA-DQ8 has been implicated as a key determinant of genetic susceptibility to human type 1 diabetes, spontaneous diabetes has been observed in HLA-DQ8 transgenic mice that lack expression of murine MHC class II molecules (mII(-/-)) only when the potent costimulatory molecule, B7.1, is transgenically expressed on pancreatic beta cells. To study the contribution of HLA-DQ8 to the development of diabetes in this model, we crossed RIP-B7.1mII(-/-) mice with a set of transgenic mouse lines that differed in their HLA-DQ8 expression patterns on APC subpopulations, in particular dendritic cells and cortical thymic epithelial cells. Surprisingly, we found that even in the absence of HLA-DQ8 and CD4 T cells, a substantial fraction of the RIP-B7.1mII(-/-) mice developed diabetes. This disease process was remarkable for not only showing insulitis, but also inflammatory destruction of the exocrine pancreas with diffusely up-regulated expression of MHC class I and ICAM-1 molecules. Expression of HLA-DQ8 markedly increased the kinetics and frequency of diabetes, with the most severe disease in the lines with the highest levels of HLA-DQ8 on cortical thymic epithelial cells and the largest numbers of CD4 T cells. However, the adoptive transfer of diabetes was not HLA-DQ8-dependent and disease could be rapidly induced with purified CD8 T cells alone. Expression of B7.1 in the target tissue can thus dramatically alter the cellular and molecular requirements for the development of autoimmunity. 相似文献
18.
F Larcher M Del Rio F Serrano J C Segovia A Ramírez A Meana A Page J L Abad M A González J Bueren A Bernad J L Jorcano 《FASEB journal》2001,15(9):1529-1538
Leptin deficiency produces a phenotype of obesity, diabetes, and infertility in the ob/ob mouse. In humans, leptin deficiency occurs in some cases of congenital obesity and in lipodystrophic disorders characterized by reduced adipose tissue and insulin resistance. Cutaneous gene therapy is considered an attractive potential method to correct circulating protein deficiencies, since gene-transferred human keratinocytes can produce and secrete gene products with systemic action. However, no studies showing correction of a systemic defect have been reported. We report the successful correction of leptin deficiency using cutaneous gene therapy in the ob/ob mouse model. As a feasibility approach, skin explants from transgenic mice overexpressing leptin were grafted on immunodeficient ob/ob mice. One month later, recipient mice reached body weight values of lean animals. Other biochemical and clinical parameters were also normalized. In a second human gene therapy approach, a retroviral vector encoding both leptin and EGFP cDNAs was used to transduce HK and, epithelial grafts enriched in high leptin-producing HK were transplanted to immunosuppressed ob/ob mice. HK-derived leptin induced body weight reduction after a drop in blood glucose and food intake. Leptin replacement through genetically engineered HK grafts provides a valuable therapeutic alternative for permanent treatment of human leptin deficiency conditions. 相似文献
19.
Manishkumar Patel Alexa Gleason Stacey O'Malley Brett Connolly Donna Suresch John Virostko Neil Phillips Shu-An Lin Tsing-Bau Chen Michael Klimas Richard J. Hargreaves Cyrille Sur David L. Williams Jr Alvin C. Powers Bohumil Bednar 《PloS one》2014,9(9)
Background
Type 2 diabetes results from failure of the β-cells to compensate for increased insulin demand due to abnormal levels of metabolic factors. The ob/ob(lep-/-) mouse has been extensively studied as an animal model of type 2 diabetes. Previous studies have shown a correlation between β-cell function and bioluminescent imaging in lean genetically engineered mice. The ability to noninvasively monitor β-cell function in ob/ob mice could provide new information on β-cell regulation in type 2 diabetes.Methods
To create the B6 Albino ob/ob MIP-luc mice (ob/ob-luc), the ob/ob mouse was crossed with the CD1 MIP-luc mouse. All mice were backcrossed over multiple generations to ensure the genetic background of the transgenic mice was over 96% similar to the background of the original ob/ob mouse. Animal weight, blood glucose levels, insulin in plasma, and in vivo bioluminescence (BLI) were monitored weekly or biweekly for up to 70 weeks of age. BL imaging was performed using IVIS Spectrum (Perkin Elmer) and calculated by integrating the bioluminescence signal between 5 and 10 min after i.v. injection of D-luciferin. Insulin immunohistochemistry determined islet beta cell count and insulin secretion assay determined islet insulin function.Results
There were significant increases in BLI and insulin levels as the ob/ob-luc mice aged while glucose levels gradually decreased. Ob/ob-luc were sacrificed at different time points to determine ex vivo BLI, islet function and total β-cell numbers using a cell counting training algorithm developed for the Vectra image analysis system (Perkin Elmer). The number of β-cells increased as the mice aged and all three ex vivo measurements correlated with BLI.Conclusions
The ob/ob-luc mice can serve as a model of metabolic stress, similar to human type 2 diabetes using BLI as a surrogate marker for β-cell function. 相似文献20.
《Bioorganic & medicinal chemistry》2014,22(7):2280-2293
Novel heteroaryl-containing benzamide derivatives were synthesized and screened using an in vitro assay measuring increases in glucose uptake and glucokinase activity stimulated by 10 mM glucose in rat hepatocytes. From a library of synthesized compounds, 3-(4-methanesulfonylphenoxy)-N-[1-(2-methoxy-ethoxymethyl)-1H-pyrazol-3-yl]-5-(3-methyl pyridin-2-yl)-benzamide (19e) was identified as a potent glucokinase activator with assays demonstrating an EC50 of 315 nM and the induction of a 2.23 fold increase in glucose uptake. Compound 19e exhibited a glucose AUC reduction of 32% (50 mg/kg) in an OGTT study with C57BL/6J mice compared to 28% for metformin (300 mg/kg). Single treatment of the compound in C57BL/J6 and ob/ob mice elicited basal glucose lowering activity, while in a two-week repeated dose study with ob/ob mice, the compound significantly decreased blood glucose levels with no evidence of hypoglycemia risk. In addition, 19e exhibited favorable pharmacokinetic parameters in mice and rats and excellent safety margins in liver and testicular toxicity studies. Compound 19e was therefore selected as a development candidate for the potential treatment of type 2 diabetes. 相似文献