共查询到20条相似文献,搜索用时 15 毫秒
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Yoshihiro Shibata Katsuji Kagechika Mitsuhiro Yamaguchi Hideo Kubo Hiroyuki Usui 《Bioorganic & medicinal chemistry letters》2012,22(23):7075-7079
We describe here the design, syntheses and structure–activity relationships (SAR) of novel zwitterionic compounds as non-thiazolidinedion (TZD) based peroxisome proliferator activated receptor (PPAR) α/γ dual agonists. We commenced the medicinal research with compound 1 originated by Eli Lilly, which was reported to possess PPAR α/γ dual agonist activity. We incorporated an amine linker and optimized it on the nitrogen of the linker, thereby envisioning the enhancement of the PPAR α/γ dual agonist activity together with altering the physicochemical properties. As a result, we could generate compounds showing the PPAR α/γ dual activity, especially among which compound 22e had a franylmethyl group on the linker and 2,6-dimethyl phenyl ring at the carboxylic acid head group furnishing a highly potent dual agonist activity, together with a great glucose lowering effect. Moreover, it remedied the lipid profile, that is, triglyceride without body weight gain in the db/db mice model. 相似文献
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Nafizal Hossain Svetlana Ivanova Åsa Sjöholm Timén Jonas Bergare Tesfaledet Mussie Lena Bergström 《Bioorganic & medicinal chemistry letters》2013,23(14):4026-4030
A series of zwitterionic spirocyclic compounds were synthesised. In vitro data revealed that these compounds were potent CCR1 antagonists. In particular, 2, 4, 11 and 20 inhibited CCR1 mediated chemotaxis of THP-1 cells in a functional assay. 相似文献
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Agustin Casimiro-Garcia Christopher F. Bigge Jo Ann Davis Teresa Padalino James Pulaski Jeffrey F. Ohren Patrick McConnell Christopher D. Kane Lori J. Royer Kimberly A. Stevens Bruce Auerbach Wendy Collard Christine McGregor Kun Song 《Bioorganic & medicinal chemistry》2009,17(20):7113-7125
The synthesis of a new series of phenylpropanoic acid derivatives incorporating an heteroaryl group at the α-position and their evaluation for binding and activation of PPARα and PPARγ are presented in this report. Among the new compounds, (S)-3-{4-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propyl]-phenyl}-2-1,2,3-triazol-2-yl-propionic acid (17j), was identified as a potent human PPARα/γ dual agonist (EC50 = 0.013 and 0.061 μM, respectively) with demonstrated oral bioavailability in rat and dog. 17j was shown to decrease insulin levels, plasma glucose, and triglycerides in the ZDF female rat model. In the human apolipoprotein A-1/CETP transgenic mouse model 17j produced increases in hApoA1 and HDL-C and decreases in plasma triglycerides. The increased potency for binding and activation of both PPAR subtypes observed with 17j when compared to previous analogs in this series was explained based on results derived from crystallographic and modeling studies. 相似文献
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David K. Williams Xiao-Tao Chen Christine Tarby Robert Kaltenbach Zhen-Wei Cai John S. Tokarski Yongmi An John S. Sack Barri Wautlet Johnni Gullo-Brown Benjamin J. Henley Robert Jeyaseelan Kristen Kellar Veeraswamy Manne George L. Trainor Louis J. Lombardo Joseph Fargnoli Robert M. Borzilleri 《Bioorganic & medicinal chemistry letters》2010,20(9):2998-3002
Biarylamine-based inhibitors of Met kinase have been identified. Lead compounds demonstrate nanomolar potency in Met kinase biochemical assays and significant activity in the Met-driven GTL-16 human gastric carcinoma cell line. X-ray crystallography revealed that these compounds adopt a bioactive conformation, in the kinase domain, consistent with that previously seen with 2-pyridone-based Met kinase inhibitors. Compound 9b demonstrated potent in vivo antitumor activity in the GTL-16 human tumor xenograft model. 相似文献
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Peng-Cheng Lv Juan Sun Yin Luo Ying Yang Hai-Liang Zhu 《Bioorganic & medicinal chemistry letters》2010,20(15):4657-4660
Fatty acid biosynthesis is essential for bacterial survival. FabH, β-ketoacyl-acyl carrier protein (ACP) synthase III, is a particularly attractive target, since it is central to the initiation of fatty acid biosynthesis and is highly conserved among Gram-positive and -negative bacteria. Fifty-six 1-acetyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazole derivatives were synthesized and developed as potent inhibitors of FabH. This inhibitor class demonstrates strong antibacterial activity. Escherichia coli FabH inhibitory assay and docking simulation indicated that the compounds 1-(5-(4-fluorophenyl)-3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone (12) and 1-(5-(4-chlorophenyl)-3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone (13) were potent inhibitors of E. coli FabH. 相似文献
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《Bioorganic & medicinal chemistry》2016,24(3):453-461
Diphenylamine derivatives have been reported with good fungicidal, insecticidal, acaricidal, rodenticidal and/or herbicidal activities. To find new lead compound of this kind, a series of novel diphenylamine derivatives were designed and synthesized by the approach of Intermediate Derivatization Methods. All compounds were identified by 1H NMR and elemental analysis. Bioassays demonstrated that some compounds substituted at 2,4,6-positions or 2,4,5-positions of phenyl ring B exhibited excellent fungicidal activities. The optimal compounds P30 and P33 showed 80% and 85% control respectively against cucumber downy mildew at 12.5 mg L−1, both 100% control against rice blast at 0.3 mg L−1 and both 100% control against cucumber gray mold at 0.9 mg L−1. The relationship between structure and fungicidal activities was discussed as well. 相似文献
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Morihisa Saitoh Jun Kunitomo Eiji Kimura Yoji Hayase Hiromi Kobayashi Noriko Uchiyama Tomohiro Kawamoto Toshimasa Tanaka Clifford D. Mol Douglas R. Dougan Garret S. Textor Gyorgy P. Snell Fumio Itoh 《Bioorganic & medicinal chemistry》2009,17(5):2017-2029
Glycogen synthase kinase-3β (GSK-3β) is implicated in abnormal hyperphosphorylation of tau protein and its inhibitors are expected to be a promising therapeutic agents for the treatment of Alzheimer’s disease. Here we report design, synthesis and structure–activity relationships of a novel series of oxadiazole derivatives as GSK-3β inhibitors. Among these inhibitors, compound 20x showed highly selective and potent GSK-3β inhibitory activity in vitro and its binding mode was determined by obtaining the X-ray co-crystal structure of 20x and GSK-3β. 相似文献
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Shankaran Kothandaraman Karla L. Donnely Gabor Butora Richard Jiao Alexander Pasternak Gregori J. Morriello Stephen D. Goble Changyou Zhou Sander G. Mills Malcolm MacCoss Pasquale P. Vicario Julia M. Ayala Julie A. DeMartino Mary Struthers Margaret A. Cascieri Lihu Yang 《Bioorganic & medicinal chemistry letters》2009,19(6):1830-1834
A series of novel 1-aminocyclopentyl-3-carboxyamides incorporating substituted tetrahydropyran moieties have been synthesized and subsequently evaluated for their antagonistic activity against the human CCR2 receptor. Among them analog 59 was found to posses potent antagonistic activity. 相似文献
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《Bioorganic & medicinal chemistry letters》2014,24(4):1098-1103
Identification of indazole derivatives acting as dual angiotensin II type 1 (AT1) receptor antagonists and partial peroxisome proliferator-activated receptor-γ (PPARγ) agonists is described.Starting from Telmisartan, we previously described that indole derivatives were very potent partial PPARγ agonists with loss of AT1 receptor antagonist activity.Design, synthesis and evaluation of new central scaffolds led us to the discovery of pyrrazolopyridine then indazole derivatives provided novel series possessing the desired dual activity.Among the new compounds, 38 was identified as a potent AT1 receptor antagonist (IC50 = 0.006 μM) and partial PPARγ agonist (EC50 = 0.25 μM, 40% max) with good oral bioavailability in rat.The dual pharmacology of compound 38 was demonstrated in two preclinical models of hypertension (SHR) and insulin resistance (Zucker fa/fa rat). 相似文献
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New series of phthalimide-sulfonylurea hybrids were prepared and examined for their in vivo anti-hyperglycemic activities in STZ-induced hyperglycemic rats using glibenclamide as a reference drug. Compounds 6c, 6d, 6g, 6h, 6j and 6k induced significant reduction in the blood glucose levels of diabetic rats ranging from 24.43 to 21.43%. Moreover, molecular docking and pharmacophore approaches were carried out to examine binding modes and fit values of the prepared compounds against PPARγ and SUR, respectively. Compounds 6c, 6d, 6j and 6m exhibited the highest binding free energies against PPARγ. Compounds 6c, 6j, 6k, 6l, and 6n showed the highest fit values against the generated pharmacophore model. Also, QSAR technique was carried out to estimate the proposed PPARγ binding affinities and insulin-secreting abilities. The synthesized compounds showed promising estimated activities. In-silico ADMET studies were performed to investigate pharmacokinetics of the synthesized compounds. They showed considerable human intestinal absorption with low BBB penetration. 相似文献
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Wen-Shan Li Shivaji V. More Chie-Hong Wang Ya Ching Jen Ching-Fa Yao Tein-Fu Wang Chin-Chun Hung Shu-Chuan Jao 《Bioorganic & medicinal chemistry letters》2010,20(3):1148-1152
This study describes the synthesis and structure–activity relationships of a series of furazan-3,4-diamide analogs. 1,2,5-Oxadiazole ring and electron-withdrawing substituent on the phenyl ring are proposed to be the important elements which contribute to a significant extent maximal potency of anti-proliferation effect. 相似文献
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John L. Gilmore James E. Sheppeck Jim Wang T.G. Murali Dhar Cullen Cavallaro Arthur M. Doweyko Lorraine Mckay Mark D. Cunningham Sium F. Habte Steven G. Nadler John H. Dodd John E. Somerville Joel C. Barrish 《Bioorganic & medicinal chemistry letters》2013,23(19):5448-5451
SAR was used to further develop an indazole class of non-steroidal glucocorticoid receptor agonists aided by a GR LBD (ligand-binding domain)-agonist co-crystal structure described in the accompanying paper. Progress towards discovering a dissociated GR agonist guided by human in vitro assays biased the optimization of this compound series towards partial agonists that possessed excellent selectivity against other nuclear hormone receptors. 相似文献
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《Bioorganic & medicinal chemistry》2014,22(21):6071-6088
Herein we describe the design, synthesis, and structure–activity relationships (SARs) of a novel phenylcyclopropane series represented by 7 and 33b as antagonists of orexin 1 and orexin 2 receptors. With 4 serving as the initial lead for the development of orexin antagonists, exploration of SAR resulted in improved binding affinity for orexin 1 and orexin 2 receptors. Among the synthesized compounds, 33b ((−)-N-(5-cyanopyridin-2-yl)-2-[(3,4-dimethoxyphenyl)oxymethyl]-2-phenylcyclopropanecarboxamide) exhibited potent in vitro activity and oral efficacy in animal sleep measurement experiments. The results of our study suggest that compound 33b may serve as a valuable template for the development of new orexin receptor antagonists. 相似文献
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Xiang-Yang Ye Stephanie Chen Hao Zhang Kenneth T. Locke Kevin O’Malley Litao Zhang Raijit Srivastava Bowman Miao Daniel Meyers Hossain Monshizadegan Debra Search Denise Grimm Rongan Zhang Jonathan Lippy Celeste Twamley Jodi K. Muckelbauer Chiehying Chang Yongmi An Vinayak Hosagrahara Lisa Zhang Joseph A. Tino 《Bioorganic & medicinal chemistry letters》2010,20(9):2933-2937
The synthesis and follow-up SAR studies of our development candidate 1 by incorporating 2-aryl-4-oxazolylmethoxy and 2-aryl-4-thiazolylmethoxy moieties into the oxybenzylglycine framework of the PPARα/γ dual agonist muraglitazar is described. SAR studies indicate that different substituents on the aryloxazole/thiazole moieties as well as the choice of carbamate substituent on the glycine moiety can significantly modulate the selectivity of PPARα versus PPARγ. Potent, highly selective PPARα activators 2a and 2l, as well as PPARα activators with significant PPARγ activity, such as 2s, were identified. The in vivo pharmacology of these compounds in preclinical animal models as well as their ADME profiles are discussed. 相似文献
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M. Paz Otero Efrén Pérez Santín Fátima Rodríguez-Barrios Belén Vaz Ángel R. de Lera 《Bioorganic & medicinal chemistry letters》2009,19(7):1883-1886
A series of analogues of the PPARγ ligand 15-deoxy-Δ12,14-PGJ2 have been synthesized by functionalization of a 5-alkyl-4-hydroxycyclopentenone core structure obtained by Piancatelli rearrangement of precursor furylcarbinol. Transient transactivation assays indicate that analogues 18 and 20 are selective nanomolar agonists of PPARγ. This subtype selectivity is lost in derivatives (23, 24) with an alkynyl (oct-1-yn) chain at the C3 position, although the cyclopentenone derivative with cis relative configuration (23) showed greater affinity for PPARα. 相似文献
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Hua Lin Christelle Doebelin Rémi Patouret Ruben D. Garcia-Ordonez Venkatasubramanian Dharmarajan Claudia Ruiz Bayona Michael D. Cameron Patrick R. Griffin Theodore M. Kamenecka 《Bioorganic & medicinal chemistry letters》2018,28(8):1313-1319
Herein we report the design and synthesis of a series of simple phenol amide ERRγ agonists based on a hydrazone lead molecule. Our structure activity relationship studies in this series revealed the phenol portion of the molecule to be required for activity. Attempts to replace the hydrazone with more suitable chemotypes led to a simple amide as a viable alternative. Differential hydrogen-deuterium exchange experiments were used to help understand the structural basis for binding to ERRγ and aid in the development of more potent ligands. 相似文献
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《Journal of enzyme inhibition and medicinal chemistry》2013,28(6):846-867
AbstractBecause of the pivotal role of cyclooxygenase (COX) in the inflammatory processes, non-steroidal anti-inflammatory drugs (NSAIDs) that suppress COX activities have been used clinically for the treatment of inflammatory diseases/syndromes; however, traditional NSAIDs exhibit serious side-effects such as gastrointestinal damage and hyper sensitivity owing to their COX-1 inhibition. Also, COX-2 inhibition-derived suppressive or preventive effects against initiation/proliferation/invasion/motility/recurrence/metastasis of various cancers/tumours such as colon, gastric, skin, lung, liver, pancreas, breast, prostate, cervical and ovarian cancers are significant. In this study, design, synthesis and structure–activity relationship (SAR) of various novel {2-[(2-, 3- and/or 4-substituted)-benzoyl, (bicyclic heterocycloalkanophenyl)carbonyl or cycloalkanecarbonyl]-(5- or 6-substituted)-1H-indol-3-yl}acetic acid analogues were investigated to seek and identify various chemotypes of potent and selective COX-2 inhibitors for the treatment of inflammatory diseases, resulting in the discovery of orally potent agents in the peripheral-inflammation model rats. The SARs and physicochemical properties for the analogues are described as significant findings. For graphical abstract: see Supplementary Material. (www.informahealthcare.com/enz) 相似文献
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Takao Kiyoi Mark York Stuart Francis Darren Edwards Glenn Walker Andrea K. Houghton Jean E. Cottney James Baker Julia M. Adam 《Bioorganic & medicinal chemistry letters》2010,20(16):4918-4921
Novel tricyclic indole-3-carboxamides were synthesized as structurally restricted analogs of bicyclic indoles, and found to be potent CB1 cannabinoid receptor agonists. The CB1 agonist activity depended on the absolute configuration of the chiral center of the tricyclic ring. The preferred enantiomer was more potent than the structurally unconstrained lead compound. Structure–activity relationships in the amide side chain of the indole C-3 position were also investigated. 相似文献