共查询到20条相似文献,搜索用时 12 毫秒
1.
Zheng Li Chunxia Liu Wei Shi Xingguang Cai Yuxuan Dai Chen Liao Wenlong Huang Hai Qian 《Bioorganic & medicinal chemistry》2018,26(3):703-711
The free fatty acid receptor 1 (FFA1) is being considered to be a novel anti-diabetic target based on its role in amplifying insulin secretion. We have previously identified several series of FFA1 agonists with different heterocyclic scaffolds. Herein, we describe the structural exploration of other heterocyclic scaffolds directed by drug-like physicochemical properties. Further structure-based design and chiral resolution provided the most potent compound 11 (EC50?=?7.9?nM), which exhibited improved lipophilicity (LogD7.4: 1.93), ligand efficiency (LE?=?0.32) and ligand lipophilicity efficiency (LLE?=?6.2). Moreover, compound 11 revealed an even better pharmacokinetic property than that of TAK-875 in terms of plasma clearance, maximum concentration, and plasma exposure. Although robust agonistic activity and PK profiles for compound 11, the glucose-lowering effects in vivo is not ideal, and the exact reason for in vitro/in vivo difference was worthy for further exploration. 相似文献
2.
《Bioorganic & medicinal chemistry》2016,24(21):5449-5454
The free fatty acid receptor 1 (FFA1/GPR40) is a novel antidiabetic target based on particular mechanism in enhancing glucose-stimulated insulin secretion. Most of reported FFA1 agonists, however, have been suffered from relatively high lipophilicity and molecular weight. Aiming to develop potent agonists with improved physicochemical property, 25 compounds containing triazole scaffold and various carboxylic acid fragments were synthesized via the click chemistry. Among them, the optimal lead compound 26 with relatively low lipophicity (Log D7.4 = 1.95) and molecular weight (Mw = 391.78) exhibited a considerable FFA1 agonistic activity (36.15%). In addition, compound 26 revealed a significant improvement in the glucose tolerance with a 21.4% and 14.2% reduction of glucose AUC0–2h in normal ICR mice and type 2 diabetic C57BL/6 mice, respectively. All of these results demonstrated that compound 26 was considered to be a promising lead compound suitable for further optimization. 相似文献
3.
《Bioorganic & medicinal chemistry》2014,22(5):1649-1666
GPR119 has emerged as an attractive target for anti-diabetic agents. We identified a structurally novel GPR119 agonist 22c that carries a 5-(methylsulfonyl)indoline motif as an early lead compound. To generate more potent compounds of this series, structural modifications were performed mainly to the central alkylene spacer. Installation of a carbonyl group and a methyl group on this spacer significantly enhanced agonistic activity, resulting in the identification of 2-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]propyl 7-fluoro-5-(methylsulfonyl)-2,3-dihydro-1H-indole-1-carboxylate (20). To further expand the chemical series of indoline-based GPR119 agonists, several heterocyclic core systems were introduced as surrogates of the carbamate spacer that mimic the presumed active conformation. This approach successfully produced an indolinylpyrimidine derivative 37, 5-(methylsulfonyl)-1-[6-({1-[3-(propan-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-4-yl}oxy)pyrimidin-4-yl]-2,3-dihydro-1H-indole, which has potent GPR119 agonist activity. In rat oral glucose tolerance tests, these two indoline-based compounds effectively lowered plasma glucose excursion and glucose-dependent insulin secretion after oral administration. 相似文献
4.
The free fatty acid receptor 1 (FFA1) is a potential target due to its function in enhancement of glucose-stimulated insulin secretion. Takeda’s compound 1 has robustly in vitro activity for FFA1, but it has been suffered from poor pharmacokinetic (PK) profiles because the phenylpropanoic acid is vulnerable to β-oxidation. To identify orally available agonists, we tried to interdict the metabolically labile group by incorporating two deuterium atoms at the α-position of phenylpropionic acid. Interestingly, the differences of physicochemical properties between hydrogen and deuterium are quite small, but there are many differences in the structure-activity relationship between phenylpropionic acid series and present deuterated series. Further optimizations of deuterated series led to the discovery of compound 18, which exhibited a superior balance in terms of in vitro activity, lipophilicity, and solubility. Better still, compound 18 revealed a lower clearance (CL = 0.44 L/h/kg), higher maximum concentration (Cmax = 7584.27 μg/L), and longer half-life (T1/2 = 4.16 h), resulting in a >23-fold exposure than compound 1. In subsequent in vivo pharmacodynamic studies, compound 18 showed a robustly glucose-lowering effect in rodent without the risk of hypoglycemia. 相似文献
5.
Shoya Yamada Fuminori Ohsawa Shuji Fujii Ryosuke Shinozaki Makoto Makishima Hirotaka Naitou Shuichi Enomoto Akihiro Tai Hiroki Kakuta 《Bioorganic & medicinal chemistry letters》2010,20(17):5143-5146
Retinoid X receptor (RXR) agonists are candidate agents for the treatment of metabolic syndrome and type 2 diabetes via activation of peroxisome proliferator-activated receptor (PPAR)/RXR or liver X receptor (LXR)/RXR-heterodimers, which control lipid and glucose metabolism. Reporter gene assays or binding assays with radiolabeled compounds are available for RXR ligand screening, but are unsuitable for high-throughput screening. Therefore, as a first step towards stabilizing a fluorescence polarization (FP) assay system for high-throughput RXR ligand screening, we synthesized fluorescent RXR ligands by modification of the lipophilic domain of RXR ligands with a carbostyril fluorophore, and selected the fluorescent RXR agonist 6-[ethyl(1-isobutyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinolin-7-yl)amino]nicotinic acid 8d for further characterization. Compound 8d showed FP in the presence of RXR and the FP was decreased in the presence of the RXR agonist LGD1069 (2). This compound should be a lead compound for use in high-throughput assay systems for screening RXR ligands. 相似文献
6.
Based on a previously reported phenoxyacetic acid scaffold, compound 7 (HWL-088) has been identified as a superior free fatty acid receptor 1 (FFA1) agonist by comprehensive structure-activity relationship study. Our results indicated that the introduction of ortho-fluoro greatly increased the activity of phenoxyacetic acid series, and the unique structure-activity relationship in biphenyl moiety is different from previously reported FFA1 agonists. Moreover, the modeling study was also performed to better understand the binding mode of present series. Compound 7 significantly improved glucose tolerance both in normal and diabetic models, and even exerted greater potential on glucose control than that of TAK-875. These findings provided a novel candidate HWL-088, which is currently in preclinical study to evaluate its potential for the treatment of diabetes. 相似文献
7.
David C. Kombo Terry A. Hauser Vladimir P. Grinevich Matthew S. Melvin Jon-Paul Strachan Serguei S. Sidach Joseph Chewning Nikolai Fedorov Kartik Tallapragada Scott R. Breining Craig H. Miller 《Bioorganic & medicinal chemistry letters》2013,23(5):1450-1455
We have carried out a pharmacological evaluation of arylmethylene quinuclidine derivatives interactions with human α3β4 nAChRs subtype, using cell-based receptor binding, calcium-influx, electrophysiological patch-clamp assays and molecular modeling techniques. We have found that the compounds bind competitively to the α3β4 receptor with micromolar affinities and some of the compounds behave as non-competitive antagonists (compounds 1, 2 and 3), displaying submicromolar IC50 values. These evidences suggest a mixed mode of action for these compounds, having interactions at the orthosteric site and more pronounced interactions at an allosteric site to block agonist effects. One of the compounds, 1-benzyl-3-(diphenylmethylene)-1-azoniabicyclo[2.2.2]octane chloride (compound 3), exhibited poorly reversible use-dependent block of α3β4 channels. We also found that removal of a phenyl group from compound 1 confers a partial agonism to the derived analog (compound 6). Introducing a hydrogen-bond acceptor into the 3-benzylidene quinuclidine derivative (compound 7) increases agonism potency at the α3β4 receptor subtype. Docking into the orthosteric binding site of a α3β4 protein structure derived by comparative modeling accurately predicted the experimentally-observed trend in binding affinity. Results supported the notion that binding requires a hydrogen bond formation between the ligand basic nitrogen and the backbone carbonyl oxygen atom of the conserved Trp-149. 相似文献
8.
Gianni Sagratini Michela Buccioni Gabriella Marucci Elena Poggesi Matthew Skorski Stefano Costanzi Dario Giardinà 《Bioorganic & medicinal chemistry》2018,26(12):3502-3513
(+)-Cyclazosin [(+)-1] is one of most selective antagonists of the α1B-adrenoceptor subtype (selectivity ratios, α1B/α1A?=?13, α1B/α1D?=?38–39). To improve the selectivity, we synthesized and pharmacologically studied the blocking activity against α1-adrenoceptors of several homochiral analogues of (+)-cyclazosin featuring different substituents on the carbonyl or amine groups, namely (?)-2, (+)-3, (?)-4–(?)-8, (+)-9. Moreover, we studied the activity of some their opposite enantiomers, namely (?)-1, (?)-3, (+)-6, and (?)-9, to evaluate the influence of stereochemistry on selectivity. The benzyloxycarbonyl and methyl (4aS,8aR) analogues (+)-3 and (?)-6 improved in a significant way the α1B selectivity of the progenitor compound: 4 and 14 time vs. the α1D subtype and 35 and 77 times vs. the α1A subtype, respectively. The study confirmed the importance of the hydrophobic cis-octahydroquinoxaline moiety of these molecules for the establishment of interactions with the α1-adrenoceptors as well that of their (4aS,8aR) stereochemistry to grant selectivity for the α1B subtype. Hypotheses on the mode of interaction of these compounds were advanced on the basis of molecular modeling studies performed on compound (+)-3. 相似文献
9.
《Bioorganic & medicinal chemistry letters》2014,24(15):3255-3259
The methyl group in cis stereochemical relationship with the basic chain of all pentatomic cyclic analogues of ACh is crucial for the agonist activity at mAChR. Among these only cevimeline (1) is employed in the treatment of xerostomia associated with Sjögren’s syndrome. Here we demonstrated that, unlike 1,3-dioxolane derivatives, in the 1,4-dioxane series the methyl group is not essential for the activation of mAChR subtypes. Docking studies, using the crystal structures of human M2 and rat M3 receptors, demonstrated that the 5-methylene group of the 1,4-dioxane nucleus of compound 10 occupies the same lipophilic pocket as the methyl group of the 1,3-dioxolane 4. 相似文献
10.
Methyl β-D-glucopyranoside tetraacetates (1) having a trideuterioacetyl group at O-2 (1a), O-3, (1b), O-4 (1c), and O-6 (1d) were synthesized by unambiguous routes to permit assignment of each individual acetoxyl-group signal in the p.m.r. spectrum of 1. The 6-acetoxyl resonance appears at lower field than signals of the other acetoxyl groups in carbon tetrachloride, chloroform-d, and methyl sulfoxide-d6, but in pyridine-d5 and benzene-d6, the 2-acetoxyl-group signal appears at lower field. The acetoxyl resonances of methyl 2,3,4-tri-O-acetyl-6-O-trityl-β-D-glucopyranoside (2), methyl 2,3,4-tri-O-acetyl-β-D-glucopyranoside (3), methyl 2,3-di-O-acetyl-4,6-O-benzylidene-β-D-glucopyranoside (5), methyl 2,3-di-O-acetyl-β-D-glucopyranoside (6), methyl 2,3,6-tri-O-acetyl-β-D-glucopyranoside (7), and methyl 2,3-di-O-acetyl-6-O-trityl-β-D-glucopyranoside (12) were assigned similarly after synthesis of the 2-(trideuterioacetyl) (2a, 3a, 5a, 6a, 7a, and 12a), 3-(trideuterioacetyl) (2b, 3b, 5b, 6b, 7b, and 12b), 4-(trideuterioacetyl) (2c and 3c), and 6-(trideuterioacetyl) (7c) analogues. In chloroform-d and benzene-d6, the 4-acetoxyl resonance appeared at about 0.3 p.p.m. to higher field than the other acetoxyl-group signals of 2. In chloroform-d and methyl sulfoxide-d6, the 3-acetoxyl resonance is observed at highest field in compounds 1, 3, and 5. In all of these instances, the 4-hydroxyl group is substituted by an acetyl or benzylidene group. When no 4-substituent is present (compounds 6, 7, and 12), the 3-acetoxyl group resonates at lower field than the other acetoxyl groups. 相似文献
11.
Alessandro Piergentili Wilma Quaglia Fabio Del Bello Mario Giannella Maria Pigini Elisabetta Barocelli Simona Bertoni Rosanna Matucci Marta Nesi Bruno Bruni Massimo Di Vaira 《Bioorganic & medicinal chemistry》2009,17(24):8174-8185
Novel analogues of cis-N,N,N-trimethyl-(6-methyl-1,4-dioxan-2-yl)methanaminium iodide (2a) were synthesized by inserting methyl groups alternatively or simultaneously in positions 5 and 6 of the 1,4-dioxane nucleus in all combinations. Their biological profile was assessed by receptor binding assays at human muscarinic M1–M5 receptors stably expressed in CHO cells and by functional studies performed on classical isolated organ preparations, namely, rabbit electrically stimulated vas deferens, and guinea pig electrically stimulated left atrium, ileum, and lung strips. The results showed that the simultaneous presence of one methyl group in both positions 5 and 6 with a trans stereochemical relationship with each other (diastereomers 4 and 5) or the geminal dimethylation in position 6 (compound 8) favour the selective activation of M3 receptors. Compounds 4, 5, and 8 might be valuable tools in the characterization of the M3 receptor, as well as provide useful information for the design and development of novel selective M3 antagonists. 相似文献
12.
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
13.
《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
14.
《Bioorganic & medicinal chemistry letters》2014,24(2):476-479
Sixteen new C-terminally modified analogues of 2, a previously described potent and selective AT2R ligand, were designed, synthesized and evaluated for their affinity to the AT2R receptor. The introduction of large, hydrophobic substituents was shown to be beneficial and the most active compound (17, Ki = 8.5 μM) was over 12-times more potent than the lead compound 2. 相似文献
15.
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
16.
《Bioorganic & medicinal chemistry》2019,27(21):115091
A structural class of 2-aminobenzoxazole derivatives possessing biphenyltetrazole was discovered to be potent human ChemR23 inhibitors. We initially tried to improve the potency of compound 1, which was found through in-house screening using the human plasmacytoid dendritic cell (pDC)-like cell line CAL-1. The introduction of a chiral methyl moiety at a benzylic position in a center of compound 1 showed a large impact on the inhibitory activity against calcium signaling of ChemR23 induced by the natural ligand chemerin. As a result of further investigations at the benzylic position, (R)-isomer 6b was found to show a 30-fold increased potency over desmethyl compound 1. In addition, an extensive structure-activity relationship study on the benzoxazole moiety successfully led to a further increase in the potency. The antagonistic effect of the compounds was based on the induction of ChemR23 internalization. In addition, we observed that compound 31, which contained an amide moiety on benzoxazole, inhibited chemotaxis of CAL-1 cells induced by chemerin in vitro. These results suggest that our ChemR23 inhibitors are attractive compounds for the treatment of pDC-related autoimmune diseases, such as systemic lupus erythematosus and psoriasis. 相似文献
17.
Kazuhiro Ikegai Masakazu Imamura Takayuki Suzuki Keita Nakanishi Takeshi Murakami Eiji Kurosaki Atsushi Noda Yoshinori Kobayashi Masayuki Yokota Tomokazu Koide Kazuhiro Kosakai Yasufumi Ohkura Makoto Takeuchi Hiroshi Tomiyama Mitsuaki Ohta 《Bioorganic & medicinal chemistry》2013,21(13):3934-3948
Here, a series of C-glucosides with azulene rings in the aglycon moiety was synthesized and the inhibitory activities toward hSGLT1 and hSGLT2 were evaluated. Starting from the azulene derivative 7 which had relatively good SGLT2 inhibitory activity, compound 8a which has a 3-[(azulen-2-yl)methyl]phenyl group was identified as a lead compound for further optimization. Introduction of a phenolic hydroxyl group onto the central benzene ring afforded a potent and selective SGLT2 inhibitor 8e, which reduced blood glucose levels in a dose-dependent manner in rodent diabetic models. A mono choline salt of 8e (YM543) was selected as a clinical candidate for use in treating type 2 diabetes mellitus. 相似文献
18.
Deyu Kong Shimeng Guo Yushe Yang Bin Guo Xin Xie Wenhao Hu 《Bioorganic & medicinal chemistry letters》2019,29(6):848-852
FFA1 (free fatty acid receptor 1) has emerged as an attractive antidiabetic target due to its role in mediating the enhancement of glucose-stimulated insulin secretion in pancreatic β cells with a low risk of hypoglycemia. Many reported FFA1 agonists possessed somewhat pharmacokinetic and/or safety issues. Herein, we describe the identification of 2,3-dihydrobenzo[b][1,4]dioxine as a novel scaffold for FFA1 agonists. Comprehensive structure-activity relationship study based on this scaffold led to the discovery of (S)-3-(4-(((S)-7-(4-methoxyphenyl)-2,3-dihydrobenzo [b][1,4]dioxin-2-yl)methoxy) phenyl)hex-4-ynoic acid (26k), which displayed a potent FFA1 agonistic activity and good pharmacokinetic profiles. Subsequent in vivo studies demonstrated that compound 26k significantly improved the glucose tolerance in ICR mice. In summary, compound 26k is a promising drug candidate for further investigation. 相似文献
19.
《Bioorganic & medicinal chemistry letters》2014,24(13):2909-2912
We designed and synthesized novel N-sulfonyl-7-azaindoline derivatives as selective M4 muscarinic acetylcholine receptor agonists. Modification of the N-carbethoxy piperidine moiety of compound 2, an M4 muscarinic acetylcholine receptor (mAChR)-preferring agonist, led to compound 1, a selective M4 mAChR agonist. Compound 1 showed a highly selective M4 mAChR agonistic activity with weak hERG inhibition in vitro. A pharmacokinetic study of compound 1 in vivo revealed good bioavailability and brain penetration in rats. Compound 1 reversed methamphetamine-induced locomotor hyperactivity in rats (1–10 mg/kg, po). 相似文献
20.
Hamid R. Hoveyda Graeme L. Fraser Ludivine Zoute Guillaume Dutheuil Didier Schils Cyrille Brantis Alexey Lapin Julien Parcq Sandra Guitard François Lenoir Mohamed El Bousmaqui Sarah Rorive Sandrine Hospied Sébastien Blanc Jérôme Bernard Frédéric Ooms Joanne C. McNelis Jerrold M. Olefsky 《Bioorganic & medicinal chemistry》2018,26(18):5169-5180
Free fatty acid-2 (FFA2) receptor is a G-protein coupled receptor of interest in the development of therapeutics in metabolic and inflammatory disease areas. The discovery and optimization of an N-thiazolylamide carboxylic acid FFA2 agonist scaffold is described. Dual key objectives were to i) evaluate the potential of this scaffold for lead optimization in particular with respect to safety de-risking physicochemical properties, i.e. lipophilicity and aromatic content, and ii) to demonstrate the utility of selected lead analogues from this scaffold in a pertinent in vivo model such as oral glucose tolerance test (OGTT). As such, a concomitant improvement in bioactivity together with lipophilic ligand efficiency (LLE) and fraction sp3 content (Fsp3) parameters guided these efforts. Compound 10 was advanced into studies in mice on the basis of its optimized profile vs initial lead 1 (ΔLLE?=?0.3, ΔFsp3?=?0.24). Although active in OGTT, 10 also displayed similar activity in the FFA2-knockout mice. Given this off-target OGTT effect, we discontinued development of this FFA2 agonist scaffold. 相似文献