共查询到20条相似文献,搜索用时 46 毫秒
1.
Takashi Nakahata Kazuyuki Tokumaru Yoshiteru Ito Naoki Ishii Masaki Setoh Yuji Shimizu Toshiya Harasawa Kazunobu Aoyama Teruki Hamada Masakuni Kori Kazuyoshi Aso 《Bioorganic & medicinal chemistry》2018,26(8):1598-1608
G-protein-coupled receptor 52 (GPR52) is classified as an orphan Gs-coupled G-protein-coupled receptor. GPR52 cancels dopamine D2 receptor signaling and activates dopamine D1/N-methyl-d-aspartate receptors via intracellular cAMP accumulation. Therefore, GPR52 agonists are expected to alleviate symptoms of psychotic disorders. A novel series of 1-(benzothiophen-7-yl)-1H-pyrazole as GPR52 agonists was designed and synthesized based on compound 1b. Compound 1b has been reported by our group as the first orally active GPR52 agonist, but high lipophilicity and poor aqueous solubility still remained as issues for candidate selection. To resolve these issues, replacement of the benzene ring at the 7-positon of compound 1b with heterocylic rings, such as pyrazole and pyridine, was greatly expected to reduce lipophilicity to levels for which calculated logD values were lower than that of compound 1b. While evaluating the pyrazole derivatives, introduction of a methyl substituent at the 3-position of the pyrazole ring led to increased GPR52 agonistic activity. Moreover, additional methyl substituent at the 5-position of the pyrazole and further introduction of hydroxy group to lower logD led to significant improvement of solubility while maintaining the activity. As a result, we identified 3-methyl-5-hydroxymethyl-1H-pyrazole derivative 17 (GPR52 EC50?=?21?nM, Emax?=?103%, logD?=?2.21, Solubility at pH 6.8?=?21?μg/mL) with potent GPR52 agonistic activity and good solubility compared to compound 1b. Furthermore, this compound 17 dose-dependently suppressed methamphetamine-induced hyperlocomotion in mice. 相似文献
2.
Yuanying Fang Jun Xu Zhifeng Li Zunhua Yang Lijuan Xiong Yi Jin Qi Wang Saisai Xie Wufu Zhu Sheng Chang 《Bioorganic & medicinal chemistry》2018,26(14):4080-4087
We described the discovery and optimization of a novel series of pyrimidopyrimidine derivatives as G-protein coupled receptor 119 (GPR119) agonists against type 2 diabetes. Most designed compounds displayed significant GPR119 agonistic activities. Optimized analogues 15a and 21e exhibited highly potent agonistic activities with single digit EC50 values (2.2?nM and 8.1?nM, respectively). Therefore, 15a and 21e were evaluated for their oral glucose tolerance test (oGTT) in C57BL/6N mice. Compound 15a reduced the blood glucose area of under curve from 0 to 2?h (AUC0–2h) to 13.5% at the dose of 15?mg/kg comparing with Metformin reduced 18% of AUC0–2h at the dose of 300?mg/kg. 相似文献
3.
Kazuhito Harada Jun Mizukami Takashi Watanabe Genki Mori Minoru Ubukata Katsunori Suwa Sumiaki Fukuda Tamotsu Negoro Motohide Sato Takashi Inaba 《Bioorganic & medicinal chemistry letters》2019,29(3):373-379
We describe here the generation of a lead compound and its optimization studies that led to the identification of a novel GPR119 agonist. Based on a spirocyclic cyclohexane structure reported in our previous work, we identified compound 8 as a lead compound, being guided by ligand-lipophilicity efficiency (LLE), which linked potency and lipophilicity. Subsequent optimization studies of 8 for improvement of solubility afforded representative 21. Compound 21 had no inhibitory activity against six CYP isoforms and showed favorable pharmacokinetic properties and hypoglycemic activity in rats. 相似文献
4.
Aman Chandra Kaushik 《Journal of biomolecular structure & dynamics》2018,36(7):1788-1805
G protein coupled receptors (GPCRs) are source machinery in signal transduction pathways and being one of the major therapeutic targets play a significant in drug discovery. GPR142, an orphan GPCR, has been implicated in the regulation of insulin, thereby having a crucial role in Type II diabetes management. Deciphering of the structures of orphan, GPCRs (O-GPCRs) offer better prospects for advancements in research in ion translocation and transduction of extracellular signals. As the crystallographic structure of GPR142 is not available in PDB, therefore, threading and ab initio-based approaches were used for 3D modeling of GPR142. Molecular dynamic simulations (900 ns) were performed on the 3D model of GPR142 and complexes of GPR142 with top five hits, obtained through virtual screening, embedded in lipid bilayer with aqueous system using OPLS force field. Compound 1, 3, and 4 may act as scaffolds for designing potential lead agonists for GPR142. The finding of GPR142 MD simulation study provides more comprehensive representation of the functional properties. The concern for Type II diabetes is increasing worldwide and successful treatment of this disease demands novel drugs with better efficacy. 相似文献
5.
《Bioorganic & medicinal chemistry letters》2014,24(13):2949-2953
The G protein-coupled receptor 40 (GPR40) mediates enhancement of glucose-stimulated insulin secretion in pancreatic β cells. The GPR40 agonist has been attracting attention as a novel insulin secretagogue with glucose dependency for the treatment of type 2 diabetes. The optimization study of compound 1 led to a potent and bioavailable GPR40 agonist 24, which showed insulin secretion and glucose lowering effects in rat OGTT. Compound 24 is a potential lead compound for a novel insulin secretagogue with a low risk of hypoglycemia. 相似文献
6.
Michiko Murakoshi Harumi Kuwabara Miyuki Nagasaki Yu Mei Xiong Jeff D. Reagan Hiroaki Maeda 《Journal of receptor and signal transduction research》2017,37(3):290-296
GPR142 is a G-protein-coupled receptor (GPCR), whose most potent and efficacious ligand has been reported as being the natural amino acid l-tryptophan. GPR142 is highly expressed in pancreatic β-cells and immune cells, suggesting the receptor may play a role in the pathogenesis and development of diabetes or inflammatory diseases. In a previous report, we developed GPR142 agonists as insulin secretagogues. In this report, we show the discovery of a selective, potent small-molecule GPR142 antagonist, CLP-3094, and its pharmacological characteristics. These data support targeting this receptor for the treatment of chronic inflammatory diseases. 相似文献
7.
Toshitake Kobayashi Satoshi Sasaki Naoki Tomita Seiji Fukui Masaharu Nakayama Atsushi Kiba Masami Kusaka Shin-ichi Matsumoto Masashi Yamaguchi Fumio Itoh Atsuo Baba 《Bioorganic & medicinal chemistry》2010,18(14):5157-5171
GPR54 is a G protein-coupled receptor (GPCR) which was formerly an orphan receptor. Recent functional study of GPR54 revealed that the receptor plays an essential role to modulate sex-hormones including GnRH. Thus, antagonists of GPR54 are expected to be novel drugs for sex-hormone dependent diseases such as prostate cancer or endometriosis. We recently reported 2-acylamino-4,6-diphenylpyridines as the first small molecule GPR54 antagonists with high potency. However, the representative compound 1 showed low brain exposure, where GPR54 acts as a modulator of gonadotropins by binding with its endogenous ligand, metastin. In order to discover compounds that have not only potent GPR54 antagonistic activity but also good brain permeability, we focused on converting the primary amine on the side chain to a secondary or tertiary amine, and finally we identified 15a containing a piperazine group. This compound exhibited high affinity to human and rat GPR54, apparent antagonistic activity, and high brain exposure. In addition, intravenous administration of 15a to castrated male rat suppressed plasma LH level, which indicates the possibility of a small molecule GPR54 antagonist as a novel drug for sex-hormone dependent diseases. 相似文献
8.
Hejun Lu Hongbo Fei Fanglong Yang Suxin Zheng Qiyue Hu Lei Zhang Jijun Yuan Jun Feng Piaoyang Sun Qing Dong 《Bioorganic & medicinal chemistry letters》2013,23(10):2920-2924
The GPR40 (FFA1) has emerged as an attractive target for a novel insulin secretagogue with glucose dependency. A series of novel orally bioavailable GPR40 agonists was discovered. SAR study and structural optimization led to identification of compounds 28a and 30a as potent GPR40 agonists with superior physiochemical properties and robust in vivo efficacy in rhesus monkeys. 相似文献
9.
《Bioorganic & medicinal chemistry letters》2019,29(14):1761-1764
The G-protein-coupled receptor 40 (GPR40) is an attractive molecular target for the treatment of type 2 diabetes mellitus. Previously, based on the natural oleic acid substrate, an exogenous ligand for this receptor, named AV1, was synthesized. In this context, here we validated the activity of AV1 as a full agonist, while the corresponding catechol analogue, named AV2, was investigated for the first time. The ligand-protein interaction between this new molecule and the receptor was highlighted in the lower portion of the GPR40 groove that generally accommodates DC260126. The functional assays performed have demonstrated that AV2 is a suitable GPR40 partial agonist, showing a therapeutic potential and representing a useful tool in the management of type 2 diabetes. 相似文献
10.
Ren Sheng Liu Yang Yanchun Zhang Enming Xing Rui Shi Xiaoan Wen Heyao Wang Hongbin Sun 《Bioorganic & medicinal chemistry letters》2018,28(15):2599-2604
GPR120 is an attractive target for the treatment of type 2 diabetes. In this study, a series of biphenyl derivatives were designed, synthesized by hybrid design. The selected compound 6a exhibited potent GPR120 agonist activity (EC50?=?93?nM) and high selectivity over GPR40. The results of oral glucose tolerance test (OGTT) demonstrated that 6a exhibited significant glucose-lowering effect in glucose-loaded ICR male mice. Analysis of the structure–activity relationship is also presented. Compound 6a deserves further biological evaluation and structural modifications. 相似文献
11.
《Bioorganic & medicinal chemistry letters》2014,24(22):5195-5198
The identification of the novel and selective GPR3 inverse agonist AF64394, the first small molecule inhibitor of GPR3 receptor function, is described. Structure activity relationships and syntheses based around AF64394 are reported. 相似文献
12.
Yuanying Fang Zunhua Yang Shankariah Gundeti Jongkook Lee Haeil Park 《Bioorganic & medicinal chemistry》2017,25(1):254-260
A series of GPR119 agonists based on a 5-nitropyrimidine scaffold bearing endo-azabicyclic substituents were synthesized and evaluated for their GPR119 agonistic activities. Most compounds exhibited much stronger EC50 values than that of oleoylethanolamide (OEA). Among them, derivatives from endo-azabicyclic alcohols displayed more potent GPR119 agonistic activities than compounds with endo-azabicyclic amines. Especially the optimized compounds (6, 7, 8, 12, 17) were shown to have potent biological activities and were identified as full agonists. Isopropyl carbamate compound 8 synthesized from endo-azabicyclic alcohol was observed to have the best EC50 value (0.6 nM). Generally 2-fluoro substitution of the aryl group at the C4 position of 5-nitropyrimidine scaffold resulted in the increase of biological activity. 相似文献
13.
Jian Zhang An-Rong Li Ming Yu Yingcai Wang Jiang Zhu Frank Kayser Julio C. Medina Karen Siegler Marion Conn Bei Shan Mark P. Grillo John Eksterowicz Peter Coward Jiwen Liu 《Bioorganic & medicinal chemistry letters》2013,23(12):3609-3613
We describe the discovery of a series of arylsulfonyl 3-(pyridin-2-yloxy)anilines as GPR119 agonists derived from compound 1. Replacement of the three methyl groups in 1 with metabolically stable moieties led to the identification of compound 34, a potent and efficacious GPR119 agonist with improved pharmacokinetic (PK) properties. 相似文献
14.
Sanath K. Meegalla Hui Huang Tonya Martin June Xu Shuyuan Zhao Jianying Liu Meghan Hall Joe Gunnet Yuanping Wang Brian Rady Jose Silva Monicah Otieno Eric Arnoult S. Paul Lee Alessandro Pocai Mark R. Player 《Bioorganic & medicinal chemistry letters》2018,28(4):720-726
Compound 12 is a GPR40 agonist that realizes the full magnitude of efficacy possible via GPR40 receptor agonism. In vitro and in vivo studies demonstrated superior glucose lowering by 12 compared to fasiglifam (TAK-875), in a glucose dependent manner. The enhanced efficacy observed with the full agonist 12 was associated with both direct and indirect stimulation of insulin secretion. 相似文献
15.
《Bioorganic & medicinal chemistry letters》2014,24(10):2383-2387
Screening hit 5 was identified in a biochemical screen for GPR119 agonists. Compound 5 was structurally novel, displayed modest biochemical activity and no oral exposure, but was structurally distinct from typical GPR119 agonist scaffolds. Systematic optimization led to compound 36 with significantly improved in vitro activity and oral exposure, to elevate GLP1 acutely in an in vivo mouse model at a dose of 10 mg/kg. 相似文献
16.
Cheng Zhu Liping Wang Yuping Zhu Zack Zhiqiang Guo Ping Liu Zhiyong Hu Jason W. Szewczyk Ling Kang Gary Chicchi Anka Ehrhardt Andrea Woods Toru Seo Morgan Woods Margaret van Heek Karen H. Dingley Jianmei Pang Gino M. Salituro Joyce Powell Scott D. Edmondson 《Bioorganic & medicinal chemistry letters》2017,27(5):1124-1128
The paper describes the SAR/SPR studies that led to the discovery of phenoxy cyclopropyl phenyl acetamide derivatives as potent and selective GPR119 agonists. Based on a cis cyclopropane scaffold discovered previously, phenyl acetamides such as compound 17 were found to have excellent GPR119 potency and improved physicochemical properties. Pharmacokinetic data of compound 17 in rat, dog and rhesus will be described. Compound 17 was suitable for QD dosing based on its predicted human half-life, and its projected human dose was much lower than that of the recently reported structurally-related benzyloxy compound 2. Compound 17 was selected as a tool compound candidate for NHP (Non-Human Primate) efficacy studies. 相似文献
17.
Tuan-Anh N. Pham Zunhua Yang Yuanying Fang Jun Luo Jongkook Lee Haeil Park 《Bioorganic & medicinal chemistry》2013,21(5):1349-1356
GPR119 agonist has emerged as a promising target for the treatment of type 2 diabetes. A series of novel 2,4-disubstituted quinazoline analogues was prepared and evaluated their agonistic activity against human GPR119. The analogues bearing azabicyclic amine substituents (12a, 12c and 12g) exhibited better EC50 values than that of OEA though they appeared to be partial agonists. 相似文献
18.
Bin Guo Shimeng Guo Jing Huang Jingya Li Jia Li Qian Chen Xianli Zhou Xin Xie Yushe Yang 《Bioorganic & medicinal chemistry》2018,26(22):5780-5791
GPR40 has become a new potential therapeutic target for the treatment of diabetes due to its role in mediating the enhancement of glucose-stimulated insulin secretion in pancreatic β cells with a low risk of hypoglycemia. As an effort to extend the chemical space and identify structurally distinct GPR40 agonists with improved liver safety, a novel series of fused-ring phenyl propanoic acid analogues were designed. Comprehensive structure-activity relationship studies around novel scaffolds were conducted and led to several analogues exhibited potent GPR40 agonistic activities and high selectivity against other fatty acid receptors. Further evaluation of pharmacokinetic (PK) profiles and in vivo efficacy identified compound 40a with excellent PK properties and significant glucose-lowering efficacy during an oral glucose tolerance test. In addition, compound 40a displayed lower hepatobiliary transporter inhibition and favorable druggability. All results indicate that compound 40a is a promising candidate for further development. 相似文献
19.
《Bioorganic & medicinal chemistry letters》2019,29(16):2100-2106
We describe here a novel GPR119 agonist 24, which showed a potent and long-acting hypoglycemic effect in rats via oral dosing. For the discovery of 24, we chose compound 5, which possessed an oxadiazole linker, as a lead compound among our spirocyclic cyclohexane GPR119 agonist series, taking into account its lower plasma protein binding nature. 3,5-Difluoro and 4-methylsulfonylmethy groups on the left side phenyl group, and a gem-difluoro group on the right side of 24 are important for its agonist potency and metabolic stability, respectively. 相似文献
20.
A novel series of fused pyrimidine derivatives were designed, synthesized and evaluated as GPR119 agonists. Among them, cyclohexene fused compounds (tetrahydroquinazolines) showed greater GPR119 agonistic activities than did dihydrocyclopentapyrimidine and tetrahydropyridopyrimidine scaffolds. Analogues (16, 19, 26, 28, 42) bearing endo-N-Boc-nortropane amine and fluoro-substituted aniline exhibited better EC50 values (0.27–1.2 μM) though they appeared to be partial agonists. 相似文献