共查询到20条相似文献,搜索用时 15 毫秒
1.
Sinz C Bittner A Brady E Candelore M Dallas-Yang Q Ding V Jiang G Lin Z 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 ER 《Bioorganic & medicinal chemistry letters》2011,21(23):7124-7130
A novel class of N-aryl-2-acylindole human glucagon receptor (hGCGR) antagonists is reported. These compounds demonstrate good pharmacokinetic profiles in multiple preclinical species. One compound from this series, indole 33, is orally active in a transgenic murine pharmacodynamic model. Furthermore, a 1mg/kg oral dose of indole 33 lowers ambient glucose levels in an ob/ob/hGCGR transgenic murine diabetes model. This compound was deemed suitable for preclinical safety studies and was found to be well tolerated in an 8-day experimental rodent tolerability study. The combination of preclinical efficacy and safety observed with compound 33 highlights the potential of this class as a treatment for type 2 diabetes. 相似文献
2.
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
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.
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
5.
Direct observation (NMR) of the efficacy of glucagon receptor antagonists in murine liver expressing the human glucagon receptor 总被引:1,自引:0,他引:1
Cohen SM Duffy JL Miller C Kirk BA Candelore MR Ding VD Kaczorowski G Tota LM Werrmann JG Wright M Parmee ER Tata JR Zhang BB 《Bioorganic & medicinal chemistry》2006,14(5):1506-1517
The demonstration of pharmacodynamic efficacy of novel chemical entities represents a formidable challenge in the early exploration of synthetic lead classes. Here, we demonstrate a technique to validate the biological efficacy of novel antagonists of the human glucagon receptor (hGCGR) in the surgically removed perfused liver prior to the optimization of the pharmacokinetic properties of the compounds. The technique involves the direct observation by (13)C NMR of the biosynthesis of [(13)C]glycogen from [(13)C]pyruvate via the gluconeogenic pathway. The rapid breakdown of [(13)C]glycogen (glycogenolysis) following the addition of 50 pM exogenous glucagon is then monitored in real time in the perfused liver by (13)C NMR. The concentration-dependent inhibition of glucagon-mediated glycogenolysis is demonstrated for both the peptidyl glucagon receptor antagonist 1 and structurally diverse synthetic antagonists 2-7. Perfused livers were obtained from a transgenic mouse strain that exclusively expresses the functional human glucagon receptor, conferring human relevance to the activity observed with glucagon receptor antagonists. This technique does not provide adequate quantitative precision for the comparative ranking of active compounds, but does afford physiological evidence of efficacy in the early development of a chemical series of antagonists. 相似文献
6.
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
7.
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
8.
Xie YF Lake K Ligsay K Komandla M Sircar I Nagarajan G Li J Xu K Parise J Schneider L Huang D Liu J Dines K Sakurai N Barbosa M Jack R 《Bioorganic & medicinal chemistry letters》2007,17(12):3367-3372
Design and synthesis of a series of 3-amino-4-(2-(2-(4-benzylpiperazin-1-yl)-2-oxoethoxy)phenylamino)cyclobutenedione derivatives as novel CCR1 antagonists are described. Structure-activity relationship studies led to the identification of compound 22, which demonstrated potent binding activity, functional antagonism of CCR1 as well as good species cross-reactivity. In addition, compound 22 also showed desirable pharmacokinetic profiles and was selected for in vivo studies in the mouse collagen-induced arthritis model. 相似文献
9.
Filipski KJ Bian J Ebner DC Lee EC Li JC Sammons MF Wright SW Stevens BD Didiuk MT Tu M Perreault C Brown J Atkinson K Tan B Salatto CT Litchfield J Pfefferkorn JA Guzman-Perez A 《Bioorganic & medicinal chemistry letters》2012,22(1):415-420
A novel series of glucagon receptor antagonists has been discovered. These pyrazole ethers and aminopyrazoles have lower molecular weight and increased polarity such that the molecules fall into better drug-like property space. This work has culminated in compounds 44 and 50 that were shown to have good pharmacokinetic attributes in dog, in contrast to rats, in which clearance was high; and compound 49, which demonstrated a dose-dependent reduction in glucose excursion in a rat glucagon challenge experiment. 相似文献
10.
Zehong Wan Dramane I. Laine Hongxing Yan Chongjie Zhu Katherine L. Widdowson Peter T. Buckley Miriam Burman James J. Foley Henry M. Sarau Dulcie B. Schmidt Edward F. Webb Kristen E. Belmonte Michael Palovich 《Bioorganic & medicinal chemistry letters》2009,19(16):4560-4562
Design and syntheses of a novel series of muscarinic antagonists are reported. These efforts have culminated in the discovery of (3-endo)-3-(2-cyano-2,2-diphenylethyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane bromide (4a) as a potent and pan-active muscarinic antagonist as well as a functionally active compound in a murine model of bronchoconstriction. The compound has also displayed pharmacokinetic characteristics suitable for inhaled delivery. 相似文献
11.
《Bioorganic & medicinal chemistry letters》2014,24(3):839-844
Identification of orally active, small molecule antagonists of the glucagon receptor represents a novel treatment paradigm for the management of type 2 diabetes mellitus. The present work discloses novel glucagon receptor antagonists, identified via conformational constraint of current existing literature antagonists. Optimization of lipophilic ligand efficiency (LLE or LipE) culminated in enantiomers (+)-trans-26 and (−)-trans-27 which exhibit good physicochemical and in vitro drug metabolism profiles. In vivo, significant pharmacokinetic differences were noted with the two enantiomers, which were primarily driven through differences in clearance rates. Enantioselective oxidation by cytochrome P450 was ruled out as a causative factor for pharmacokinetic differences. 相似文献
12.
McAtee JJ Dodson JW Dowdell SE Erhard K Girard GR Goodman KB Hilfiker MA Jin J Sehon CA Sha D Shi D Wang F Wang GZ Wang N Wang Y Viet AQ Yuan CC Zhang D Aiyar NV Behm DJ Carballo LH Evans CA Fries HE Nagilla R Roethke TJ Xu X Douglas SA Neeb MJ 《Bioorganic & medicinal chemistry letters》2008,18(13):3716-3719
Lead compound 1 was successfully redesigned to provide compounds with improved pharmacokinetic profiles for this series of human urotensin-II antagonists. Replacement of the 2-pyrrolidinylmethyl-3-phenyl-piperidine core of 1 with a substituted N-methyl-2-(1-pyrrolidinyl)ethanamine core as in compound 7 resulted in compounds with improved oral bioavailability in rats. The relationship between stereochemistry and selectivity for hUT over the kappa-opioid receptor was also explored. 相似文献
13.
《Bioorganic & medicinal chemistry letters》2019,29(20):126668
Type 2 diabetes mellitus (T2DM) is characterized by chronically elevated plasma glucose levels. The inhibition of glucagon-induced hepatic glucose output via antagonism of the glucagon receptor (GCGR) using a small-molecule antagonist is a promising mechanism for improving glycemic control in the diabetic state. The present work discloses the discovery of indazole-based β-alanine derivatives as potent GCGR antagonists through an efficient enantioselective synthesis and structure-activity relationship (SAR) exploration and optimization. Compounds within this class exhibited excellent pharmacokinetic properties in multiple preclinical species. In an acute dog glucagon challenge test, compound 13K significantly inhibited glucagon-mediated blood glucose increase when dosed orally at 10 mg/kg. 相似文献
14.
《Bioorganic & medicinal chemistry letters》2019,29(15):1974-1980
A novel series of indazole/indole derivatives were discovered as glucagon receptor (GCGR) antagonists through scaffold hopping based on two literature leads: MK-0893 and LY-2409021. Further structure-activity relationship (SAR) exploration and optimization led to the discovery of multiple potent GCGR antagonists with excellent pharmacokinetic properties in mice and rats, including low systemic clearance, long elimination half-life, and good oral bioavailability. These potent GCGR antagonists could be used for potential treatment of type II diabetes. 相似文献
15.
Zhu GD Gong J Claiborne A Woods KW Gandhi VB Thomas S Luo Y Liu X Shi Y Guan R Magnone SR Klinghofer V Johnson EF Bouska J Shoemaker A Oleksijew A Stoll VS De Jong R Oltersdorf T Li Q Rosenberg SH Giranda VL 《Bioorganic & medicinal chemistry letters》2006,16(12):3150-3155
The structure-activity relationships of a series of isoquinoline-pyridine-based protein kinase B/Akt antagonists have been investigated in an effort to improve the major short-comings of the lead compound 3, including poor pharmacokinetic profiles in several species (e.g., mouse i.v. t(1/2) = 0.3 h, p.o. F = 0%). Chlorination at C-1 position of the isoquinoline improved its pharmacokinetic property in mice (i.v. t(1/2) = 5.0 h, p.o. F = 51%) but resulted in >500-fold drop in potency. In a mouse MiaPaCa-2 xenograft model, an amino analog 10y significantly slowed the tumor growth, however was accompanied by toxicity. 相似文献
16.
Silverman LS Caldwell JP Greenlee WJ Kiselgof E Matasi JJ Tulshian DB Arik L Foster C Bertorelli R Monopoli A Ongini E 《Bioorganic & medicinal chemistry letters》2007,17(6):1659-1662
A novel series of 3-substituted-8-aryl-[1,2,4]-triazolo[5,1-i]purin-5-amine analogs related to Sch 58261 was synthesized in order to identify potent adenosine A(2A) receptor antagonists with improved selectivity over the A(1) receptor, physiochemical properties, and pharmacokinetic profiles as compared to those of Sch 58261. As a result of structural modifications, numerous analogs with excellent in vitro binding affinities and selectivities were identified. Moreover, compound 27 displayed both superior in vitro and highly promising in vivo profiles. 相似文献
17.
《Bioorganic & medicinal chemistry letters》2014,24(13):2963-2968
Modification of a series of P2Y12 receptor antagonists by replacement of the ester functionality was aimed at minimizing the risk of in vivo metabolic instability and pharmacokinetic variability. The resulting ketones were then optimized for their P2Y12 antagonistic and anticoagulation effects in combination with their physicochemical and absorption profiles. The most promising compound showed very potent antiplatelet action in vivo. However, pharmacodynamic–pharmacokinetic analysis did not reveal a significant separation between its anti-platelet and bleeding effects. The relevance of receptor binding kinetics to the in vivo profile is described. 相似文献
18.
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
19.
Yoshikazu Arai Yohei Kiyotsuka Kousei Shimada Kazunori Oyama Masanori Izumi 《Bioorganic & medicinal chemistry letters》2019,29(18):2613-2616
The discovery and optimization of a novel series of PTHR1 antagonists are described. Starting from known PTHR1 antagonists, we identified more potent 1,4-benzodiazepin-2-one derivatives by means of a scaffold-hopping approach. The representative compound 23 (DS08210767) exhibited nanomolar-level PTHR1 antagonist activity and potential oral bioavailability in a pharmacokinetic study. 相似文献
20.
Xiaohui Du Darin J. Gustin Xiaoqi Chen Jason Duquette Lawrence R. McGee Zhulun Wang Karen Ebsworth Kirk Henne Bryan Lemon Ji Ma Shichang Miao Emmanuel Sabalan Timothy J. Sullivan George Tonn Tassie L. Collins Julio C. Medina 《Bioorganic & medicinal chemistry letters》2009,19(17):5200-5204
A general way of improving the potency of CXCR3 antagonists with fused hetero-bicyclic cores was identified. Optimization efforts led to the discovery of a series of imidazo-pyrazine derivatives with improved pharmacokinetic properties in addition to increased potency. The efficacy of the lead compound 21 is evaluated in a mouse lung inflammation model. 相似文献