共查询到20条相似文献,搜索用时 0 毫秒
1.
Xu H Zhang H Luan L Xu Y Li C Wang Y Han F Yang T Ren F Xiang JN Elliott JD Zhao Y Guo TB Lu H Zhang W Hirst D Lindon M Lin X 《Bioorganic & medicinal chemistry letters》2012,22(7):2456-2459
High-throughput screening of GSK compound collection led to the discovery of a novel series of thiadiazole amides as potent and S1P(3)-sparing sphingosine-1-phosphate 1 (S1P(1)) receptor agonists. Synthesis, structure and activity relationship, selectivity, and some developability properties are described. 相似文献
2.
Jérôme Amaudrut Maria A. Argiriadi Martine Barth Eric C. Breinlinger Didier Bressac Pierre Broqua David J. Calderwood Mohamed Chatar Kevin P. Cusack Stephen B. Gauld Sébastien Jacquet Rajesh V. Kamath Michael E. Kort Valérie Lepais Jean-Michel Luccarini Philippe Masson Christian Montalbetti Laurent Mounier Craig D. Wallace 《Bioorganic & medicinal chemistry letters》2019,29(14):1799-1806
A high-throughput screen against Inventiva’s compound library using a Gal4/RORγ-LBD luciferase reporter gene assay led to the discovery of a new series of quinoline sulphonamides as RORγ inhibitors, eventually giving rise to a lead compound having an interesting in vivo profile after oral administration. This lead was evaluated in a target engagement model in mouse, where it reduced IL-17 cytokine production after immune challenge. It also proved to be active in a multiple sclerosis model (EAE) where it reduced the disease score. The synthesis, structure activity relationship (SAR) and biological activity of these derivatives is described herein. 相似文献
3.
A new series of PPARγ partial agonists, 1,3-diphenyl-1H-pyrazole derivatives, were identified using an improved virtual screening scheme combining ligand-centric and receptor-centric methods. An in vitro assay confirmed the nanomolar binding affinity of 1,3-diphenyl-1H-pyrazole derivatives such as SP3415. We also characterized the competitive antagonism of SP3415 against rosiglitazone at micromolar concentrations. They showed a PPARγ partial agonistic activity similar to that of a known PPARγ drug, pioglitazone, in a cell-based transactivation assay. Furthermore, the structure-activity relationships of the pyrazole derivatives were investigated through comparative molecular field analysis and binding mode analysis, which provided new insight concerning their partial agonistic effect on PPARγ. 相似文献
4.
Luckhurst CA Stein LA Furber M Webb N Ratcliffe MJ Allenby G Botterell S Tomlinson W Martin B Walding A 《Bioorganic & medicinal chemistry letters》2011,21(1):492-496
Small molecule isoindoline and tetrahydroisoquinoline derivatives have been identified as selective agonists of human peroxisome proliferator-activated receptor δ (PPARδ. Compound 18 demonstrated efficacy in a biomarker for increased fatty acid oxidation, with upregulation of pyruvate dehydrogenase kinase, isozyme 4 (PDK4) in human primary myotubes. 相似文献
5.
Noel R Song X Shin Y Banerjee S Kojetin D Lin L Ruiz CH Cameron MD Burris TP Kamenecka TM 《Bioorganic & medicinal chemistry letters》2012,22(11):3739-3742
The design and synthesis of a novel series of Rev-erbα agonists is described. The development and optimization of the tetrahydroisoquinoline series was carried out from an earlier acyclic series of Rev-erbα agonists. Through the optimization of the scaffold 1, several potent compounds with good in vivo profiles were discovered. 相似文献
6.
Isaac E. Marx Erin F. DiMauro Alan Cheng Renee Emkey Stephen A. Hitchcock Liyue Huang Ming Y. Huang Jason Human Josie H. Lee Xingwen Li Matthew W. Martin Ryan D. White Robert T. Fremeau Vinod F. Patel 《Bioorganic & medicinal chemistry letters》2009,19(1):31-35
A series of α-amidosulfones were found to be potent and selective agonists of CB2. The discovery, synthesis, and structure–activity relationships of this series of agonists are reported. In addition, the pharmacokinetic properties of the most promising compounds are profiled. 相似文献
7.
Tatsuya Maruyama Kenichi Onda Masahiko Hayakawa Norio Seki Takumi Takahashi Hiroyuki Moritomo Takayuki Suzuki Tetsuo Matsui Toshiyuki Takasu Itsuro Nagase Mitsuaki Ohta 《Bioorganic & medicinal chemistry》2009,17(9):3283-3294
In the search for potent and selective human β3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, a novel series of phenoxypropanolamine derivatives containing acetanilides were prepared and their biological activities were evaluated at the human β3-, β2-, and β1-ARs. Several of the analogues (21a, 21b, and 27a) exhibited potent agonistic activity at the β3-AR. Among the compounds described herein, the N-methyl-1-benzylimidazol-2-ylacetanilide derivative (21b) was found to be the most potent and selective β3-AR agonist, with an EC50 value of 0.28 μM and no agonistic activity for either the β1- or β2-AR. In addition, 21b showed significant hypoglycemic activity in a rodent diabetic model. 相似文献
8.
Tomoaki Koshizawa Toshiharu Morimoto Gen Watanabe Tomoaki Fukuda Nao Yamasaki Sumihiko Hagita Yoshikazu Sawada Ayumu Okuda Kimiyuki Shibuya Tadaaki Ohgiya 《Bioorganic & medicinal chemistry letters》2018,28(19):3236-3241
Herein, we describe the discovery, synthesis, and evaluation of a novel series of spiro[chromane-2,4′-piperidine] derivatives as G-protein-coupled receptor 119 agonists. Their initial design exploited the conformational restriction in the linker-to-tail moiety, which was a key concept in this study, to give lead compound 11 (EC50?=?369?nM, Emax?=?82%). An extensive structure–activity relationship study resulted in the identification of the optimized drug candidate (R)-29 (EC50?=?54?nM, Emax?=?181%). The defining structural features of the series were a terminal benzyl-type bulky substituent and a methylene linker between the sulfonyl and phenyl groups, both of which were in the head moiety as well as the spiro-type scaffold in the linker-to-tail moiety. An in vivo oral glucose-tolerance test using C57BL/6N mice showed that (R)-29 reduced glucose excursion at a dose of 3?mg/kg in a dose-dependent manner. 相似文献
9.
Hudkins RL Aimone LD Bailey TR Bendesky RJ Dandu RR Dunn D Gruner JA Josef KA Lin YG Lyons J Marcy VR Mathiasen JR Sundar BG Tao M Zulli AL Raddatz R Bacon ER 《Bioorganic & medicinal chemistry letters》2011,21(18):5493-5497
H(3)R structure-activity relationships on a novel class of pyridazin-3-one H(3)R antagonists/inverse agonists are disclosed. Modifications of the pyridazinone core, central phenyl ring and linker led to the identification of molecules with excellent target potency, selectivity and pharmacokinetic properties. Compounds 13 and 21 displayed potent functional H(3)R antagonism in vivo in the rat dipsogenia model and demonstrated robust wake activity in the rat EEG/EMG model. 相似文献
10.
Josep Bonjoch Faïza Diaba Lluís Pagès Daniel Pérez Lidia Soca Montserrat Miralpeix Dolors Vilella Paquita Anton Carles Puig 《Bioorganic & medicinal chemistry letters》2009,19(15):4299-4302
A γ-carboline series of cysLT1 receptor antagonists has been prepared. Some of the compounds show good potencies both, in vitro and in vivo, compared to the standard compounds. 相似文献
11.
Pennington LD Croghan MD Sham KK Pickrell AJ Harrington PE Frohn MJ Lanman BA Reed AB Lee MR Xu H McElvain M Xu Y Zhang X Fiorino M Horner M Morrison HG Arnett HA Fotsch C Tasker AS Wong M Cee VJ 《Bioorganic & medicinal chemistry letters》2012,22(1):527-531
We reveal how a N-scan SAR strategy (systematic substitution of each CH group with a N atom) was employed for quinolinone-based S1P(1) agonist 5 to modulate physicochemical properties and optimize in vitro and in vivo activity. The diaza-analog 17 displays improved potency (hS1P(1) RI; 17: EC(50)=0.020 μM, 120% efficacy; 5: EC(50)=0.070 μM, 110% efficacy) and selectivity (hS1P(3) Ca(2+) flux; 17: EC(50) >25 μM; 5: EC(50)=1.5 μM, 92% efficacy), as well as enhanced pharmacokinetics (17: CL=0.15 L/h/kg, V(dss)=5.1L/kg, T(1/2)=24h, %F=110; 5: CL=0.93L/h/kg, V(dss)=11L/kg, T(1/2)=15 h, %F=60) and pharmacodynamics (17: 1.0mg/kg po, 24h PLC POC=-67%; 5: 3mg/kg po, 24h PLC POC=-51%) in rat. 相似文献
12.
Toshihiro Hamajima Fumie Takahashi Koji Kato Koichiro Mukoyoshi Kousei Yoshihara Susumu Yamaki Yukihito Sugano Ayako Moritomo Kaoru Yamagami Koji Yokoo Hidehiko Fukahori 《Bioorganic & medicinal chemistry》2018,26(9):2410-2419
Phosphatidylinositol-3-kinase (PI3K)δ inhibition is one of the most attractive approaches to the treatment of autoimmune diseases and leukocyte malignancies. Through the exploration of pyrazolopyridine derivatives as potential PI3Kδ inhibitors, compound 12a was identified as a potent PI3Kδ inhibitor but suffered from poor oral exposure in mice. With a modified amide linkage group, compound 15a was developed as an orally available PI3Kδ inhibitor with reduced selectivity against other PI3Ks. To improve the trade-off between selectivity and PK profile, structure–activity relationship (SAR) studies of terminal substituents on the pyrolidine ring were conducted. As a result, we developed potent PI3Kδ inhibitors with good oral availability. In particular, the representative compound 15j showed excellent selectivity for PI3Kδ over other PI3Ks with good oral exposure in mice. 相似文献
13.
Sun D Wang Z Caille S DeGraffenreid M Gonzalez-Lopez de Turiso F Hungate R Jaen JC Jiang B Julian LD Kelly R McMinn DL Kaizerman J Rew Y Sudom A Tu H Ursu S Walker N Willcockson M Yan X Ye Q Powers JP 《Bioorganic & medicinal chemistry letters》2011,21(1):405-410
The synthesis and SAR of a series of 4,4-disubstituted cyclohexylbenzamide inhibitors of 11β-HSD1 are described. Optimization rapidly led to potent, highly selective, and orally bioavailable inhibitors demonstrating efficacy in both rat and non-human primate ex vivo pharmacodynamic models. 相似文献
14.
Yann Lamotte Paul Martres Nicolas Faucher Alain Laroze Didier Grillot Nicolas Ancellin Yannick Saintillan Véronique Beneton Robert T. Gampe 《Bioorganic & medicinal chemistry letters》2010,20(4):1399-1404
Starting from the structure of Telmisartan, a new series of potent and selective PPARγ modulators was identified. The synthesis, in vitro and in vivo evaluation of the most potent compounds are reported and the X-ray structure of compound 7b bound to the PPARγ ligand binding domain is described. 相似文献
15.
《Bioorganic & medicinal chemistry》2014,22(15):4119-4123
A series of thiobarbituric acid derivatives 1–27 were synthesized and evaluated for their urease inhibitory potential. Exciting results were obtained from the screening of these compounds 1–27. Compounds 5, 7, 8, 11, 16, 17, 22, 23 and 24 showed excellent urease inhibition with IC50 values 18.1 ± 0.52, 16.0 ± 0.45, 16.0 ± 0.22, 14.3 ± 0.27, 6.7 ± 0.27, 10.6 ± 0.17, 19.2 ± 0.29, 18.2 ± 0.76 and 1.61 ± 0.18 μM, respectively, much better than the standard urease inhibitor thiourea (IC50 = 21 ± 0.11 μM). Compound 3, 4, 10, and 26 exhibited comparable activities to the standard with IC50 values 21.4 ± 1.04 and 21.5 ± 0.61μM, 22.8 ± 0.32, 25.2 ± 0.63, respectively. However the remaining compounds also showed prominent inhibitory potential The structure–activity relationship was established for these compounds. This study identified a novel class of urease inhibitors. The structures of all compounds were confirmed through spectroscopic techniques such as EI-MS and 1H NMR. 相似文献
16.
Shah MR Arfan M Amin H Hussain Z Qadir MI Choudhary MI VanDerveer D Mesaik MA Soomro S Jabeen A Khan IU 《Bioorganic & medicinal chemistry letters》2012,22(8):2744-2747
Bergenin is an isocoumarin natural product which aides in fat loss, healthy weight maintenance, enhancing the lipolytic effects of norepinephrine, inhibiting the formation of interleukin 1α and cyclooxygenases-2. Here we describe the anti-inflammatory activity of new bergenin derivatives 1-15 in the respiratory burst assay. Bergenin was isolated from the crude extract of Mallotus philippenensis after repeated column chromatography and was then subjected to chemical derivatization. The structures of all compounds were elucidated by NMR and mass spectroscopic techniques. Compound 2 was also studied using single crystal X-ray diffraction. Compounds 4, (54.5±2.2%) 5 (47.5±0.5%) 5, and 15 (86.8±1.9%) showed significant (P≤0.005) NO inhibitory activities whereas 6, 7, 11, 12 and 13 displayed moderate inhibitory activities that ranges between 16% and 31%. Furthermore compounds 4 and 15, were discovered as significant (P≤0.005) TNF-α inhibitors with 98% and 96% inhibition, respectively, while compounds 3, 5, 7, 8, 11, and 12 showed low level of TNF-α inhibition (0.4-28%). Compounds 8, 13 and 15 exhibited moderate anti-inflammatory IC(50) activities with 212, 222, and 253 μM, respectively, compared to the standard anti-inflammatory drug indomethacin as well as the parent bergenin compound. No cytotoxic effects could be detected when the compounds were tested on 3T3 cells up to concentrations of 100 μM. 相似文献
17.
Hyeju Jo Minho Choi Jaeuk Sim Mayavan Viji Siyuan Li Young Hee Lee Youngsoo Kim Seung-Yong Seo Yuanyuan Zhou Kiho Lee Wun-Jae Kim Jin Tae Hong Heesoon Lee Jae-Kyung Jung 《Bioorganic & medicinal chemistry letters》2017,27(15):3374-3377
We have disclosed our effort to develop caffeic acid derivatives as potent and non-toxic inhibitors of α-MSH-stimulated melanogenesis to treat pigmentation disorders and skin medication including a cosmetic skin-whitening agent. The SAR studies revealed that cyclohexyl ester and secondary amide derivatives of caffeic acid showed significant inhibitory activities. 相似文献
18.
Bin Ma Kevin M. Guckian Edward Yin-Shiang Lin Wen-Cherng Lee Daniel Scott Gnanasambandam Kumaravel Timothy L. Macdonald Kevin R. Lynch Cheryl Black Sowmya Chollate Kyungmin Hahm Gregg Hetu Ping Jin Yi Luo Ellen Rohde Anthony Rossomando Robert Scannevin Joy Wang Chunhua Yang 《Bioorganic & medicinal chemistry letters》2010,20(7):2264-2269
Modifying FTY720, an immunosuppressant modulator, led to a new series of well phosphorylated tetralin analogs as potent S1P1 receptor agonists. The stereochemistry effect of tetralin ring was probed, and (?)-(R)-2-amino-2-((S)-6-octyl-1,2,3,4-tetrahydronaphthalen-2-yl)propan-1-ol was identified as a good SphK2 substrate and potent S1P1 agonist with good oral bioavailability. 相似文献
19.
Dong Xiao Cheng Wang Anandan Palani Hon-Chung Tsui Gregory Reichard Sunil Paliwal Neng-Yang Shih Robert Aslanian Ruth Duffy Jean Lachowicz Geoffrey Varty Cynthia Morgan Fei Liu Amin Nomeir 《Bioorganic & medicinal chemistry letters》2010,20(21):6313-6315
Modification of prototype NK1 antagonist 2 resulted in the synthesis of a series of simple amides 6 and retroamides 9. These compounds were shown to be potent and orally active NK1 antagonists. 相似文献
20.
Fused tricyclic indoles as S1P₁ agonists with robust efficacy in animal models of autoimmune disease
Buzard DJ Han S Lopez L Kawasaki A Moody J Thoresen L Ullman B Lehmann J Calderon I Zhu X Gharbaoui T Sengupta D Krishnan A Gao Y Edwards J Barden J Morgan M Usmani K Chen C Sadeque A Thatte J Solomon M Fu L Whelan K Liu L Al-Shamma H Gatlin J Le M Xing C Espinola S Jones RM 《Bioorganic & medicinal chemistry letters》2012,22(13):4404-4409
Two series of fused tricyclic indoles were identified as potent and selective S1P(1) agonists. In vivo these agonists produced a significant reduction in circulating lymphocytes which translated into robust efficacy in several rodent models of autoimmune disease. Importantly, these agonists were devoid of any activity at the S1P(3) receptor in vitro, and correspondingly did not produce S1P(3) mediated bradycardia in telemeterized rat. 相似文献