共查询到20条相似文献,搜索用时 0 毫秒
1.
Shankar BB Lavey BJ Zhou G Spitler JA Tong L Rizvi R Yang DY Wolin R Kozlowski JA Shih NY Wu J Hipkin RW Gonsiorek W Lunn CA 《Bioorganic & medicinal chemistry letters》2005,15(20):4417-4420
We recently reported that compound 1 is a potent inhibitor of the CB2 receptor with high selectivity over CB1. This paper describes the SAR development for this class of compounds. Variation of the substitution pattern on the aromatic rings, as well as the groups linking them together, led to sub-nanomolar inhibitors of the CB2 receptor, with high selectivity over CB1. 相似文献
2.
Masayuki Fujinaga Katsushi Kumata Kazuhiko Yanamoto Kazunori Kawamura Tomoteru Yamasaki Joji Yui Akiko Hatori Masanao Ogawa Yuichiro Yoshida Nobuki Nengaki Jun Maeda Ming-Rong Zhang 《Bioorganic & medicinal chemistry letters》2010,20(5):1565-1568
Two novel triaryl ligands 2 and 5 with potent in vitro binding affinities for the cannabinoid subtype-2 (CB2) receptor were labeled with a positron-emitting radioactive nuclide 11C. Radioligands [11C]2, [11C]5, and their analogs [11C]3 and [11C]4 were synthesized by O-[11C]methylation of their corresponding phenol precursors with [11C]CH3I. [11C]2–5 had relatively high uptakes (>1.2% injected dose/g tissue) in mouse brains. 相似文献
3.
Ling Tong B.B. Shankar Lei Chen Razia Rizvi Joseph Kelly Eric Gilbert Chunli Huang De-Yi Yang Joseph A. Kozlowski N.-Y. Shih W. Gonsiorek R. William Hipkin Asra Malikzay Charles A. Lunn Daniel J. Lundell 《Bioorganic & medicinal chemistry letters》2010,20(22):6785-6789
We report further expansion of the structure activity relationship (SAR) on the triaryl bis sulfone class of compounds (I), which are potent CB2 receptor ligands with excellent selectivity over the CB1 receptor. This study was extended to B ring changes, followed by simultaneous optimization of the A-, B-, and C-rings. Compound 42 has excellent CB2 potency, selectivity and rat exposure. 相似文献
4.
Smith RA Fathi Z Achebe F Akuche C Brown SE Choi S Fan J Jenkins S Kluender HC Konkar A Lavoie R Mays R Natoli J O'Connor SJ Ortiz AA Su N Taing C Tomlinson S Tritto T Wang G Wirtz SN Wong W Yang XF Ying S Zhang Z 《Bioorganic & medicinal chemistry letters》2007,17(10):2706-2711
Several imidazole-based cyclohexyl amides were identified as potent CB-1 antagonists, but they exhibited poor oral exposure in rodents. Incorporation of a hydroxyl moiety on the cyclohexyl ring provided a dramatic improvement in oral exposure, together with a ca. 10-fold decrease in potency. Further optimization provided the imidazole 2-hydroxy-cyclohexyl amide 45, which exhibited hCB-1 K(i)=3.7nM, and caused significant appetite suppression and robust, dose-dependent reduction of body weight gain in industry-standard rat models. 相似文献
5.
Armstrong HE Galka A Lin LS Lanza TJ Jewell JP Shah SK Guthikonda R Truong Q Chang LL Quaker G Colandrea VJ Tong X Wang J Xu S Fong TM Shen CP Lao J Chen J Shearman LP Stribling DS Rosko K Strack A Ha S Van der Ploeg L Goulet MT Hagmann WK 《Bioorganic & medicinal chemistry letters》2007,17(8):2184-2187
Sulfonamide analogues of the potent CB1R inverse agonist taranabant were prepared and optimized for potency and selectivity for CB1R. They were variably more potent than the corresponding amide analogues. The most potent representative 22 had good pharmacokinetic and brain levels, but was modestly active in blocking CB1R agonist-mediated hypothermia. 相似文献
6.
Worm K Zhou QJ Saeui CT Green RC Cassel JA Stabley GJ DeHaven RN Conway-James N LaBuda CJ Koblish M Little PJ Dolle RE 《Bioorganic & medicinal chemistry letters》2008,18(9):2830-2835
Sulfamoyl benzamides were identified as a novel series of cannabinoid receptor ligands. Starting from a screening hit 8 that had modest affinity for the cannabinoid CB2 receptor, a parallel synthesis approach and initial SAR are described, leading to compound 27 with 120-fold functional selectivity for the CB2 receptor. This compound produced robust antiallodynic activity in rodent models of postoperative pain and neuropathic pain without traditional cannabinergic side effects. 相似文献
7.
Lavey BJ Kozlowski JA Hipkin RW Gonsiorek W Lundell DJ Piwinski JJ Narula S Lunn CA 《Bioorganic & medicinal chemistry letters》2005,15(3):783-786
A novel class of cannabinoid CB2 receptor ligands is described. These triaryl bis-sulfones are nanomolar inhibitors of the CB2 receptor and show high selectivity over the cannabinoid CB1 receptor. One example of this new class decreases ligand-induced GTPgammaS binding to recombinant CB2 cell membranes, identifying the compound as a CB2-selective inverse agonist. 相似文献
8.
Eric J. Gilbert Guowei Zhou Michael K.C. Wong Ling Tong Bandarpalle B. Shankar Chunli Huang Joseph Kelly Brian J. Lavey Stuart W. McCombie Lei Chen Razia Rizvi Youhao Dong Youheng Shu Joseph A. Kozlowski Neng-Yang Shih R. William Hipkin Waldemar Gonsiorek Asra Malikzay Charles A. Lunn Len Favreau Daniel J. Lundell 《Bioorganic & medicinal chemistry letters》2010,20(2):608-611
The triaryl bis-sulfone 1 was modified by converting the aryl A-ring to a piperidine ring. The piperidine ring was further elaborated to a spirocyclopropyl piperidine moiety. The effect on CB2 binding potency, rat calcium channel affinity, and CYP 2C9 inhibition is described. 相似文献
9.
Nitrosamines as nicotinic receptor ligands 总被引:1,自引:0,他引:1
Schuller HM 《Life sciences》2007,80(24-25):2274-2280
Nitrosamines are carcinogens formed in the mammalian organism from amine precursors contained in food, beverages, cosmetics and drugs. The potent carcinogen, NNK, and the weaker carcinogen, NNN, are nitrosamines formed from nicotine. Metabolites of the nitrosamines react with DNA to form adducts responsible for genotoxic effects. We have identified NNK as a high affinity agonist for the alpha7 nicotinic acetylcholine receptor (alpha7nAChR) whereas NNN bound with high affinity to epibatidine-sensitive nAChRs. Diethylnitrosamine (DEN) bound to both receptors but with lower affinity. High levels of the alpha7nAChR were expressed in human small cell lung cancer (SCLC) cell lines and in hamster pulmonary neuroendocrine cells (PNECs), which serve as a model for the cell of origin of human SCLC. Exposure of SCLC or PNECs to NNK or nicotine increased expression of the alpha7nAChR and caused influx of Ca(2+), activation of PKC, Raf-1, ERK1/2, and c-myc, resulting in the stimulation of cell proliferation. Signaling via the alpha7nAChR was enhanced when cells were maintained in an environment of 10-15% CO(2) similar to that in the diseased lung. Hamsters with hyperoxia-induced pulmonary fibrosis developed neuroendocrine lung carcinomas similar to human SCLC when treated with NNK, DEN, or nicotine. The development of the NNK-induced tumors was prevented by green tea or theophylline. The beta-adrenergic receptor agonist, isoproterenol or theophylline blocked NNK-induced cell proliferation in vitro. NNK and nicotine-induced hyperactivity of the alpha7nAChR/RAF/ERK1/2 pathway thus appears to play a crucial role in the development of SCLC in smokers and could be targeted for cancer prevention. 相似文献
10.
11.
John A. Lowe III Weimin Qian Pamela J. Scott Stafford McLean Dianne K. Bryce Rosemary T. Crawford Jon Bordner 《Bioorganic & medicinal chemistry letters》1994,4(24):2877-2882
A series of 5,7-diphenyl-3-ureidohexahydroazepin-2-one cholecystokinin-B (CCK-B) receptor antagonists was synthesized using Beckmann ring expansion of a suitable 2,4-diphenylcyclohexanone as a key step. SAR studies revealed the importance of the 5-aryl group for high and selective CCK-B receptor affinity, as illustrated in compound (−)-10i (CCK-B IC50 = 6.8 nM). 相似文献
12.
Faghih R Dwight W Vasudevan A Dinges J Conner SE Esbenshade TA Bennani YL Hancock AA 《Bioorganic & medicinal chemistry letters》2002,12(21):3077-3079
Biaryl nitrile amines were prepared and found to have high affinity and selectivity for human and rat histamine H(3) receptors. 相似文献
13.
Gil Nam Lee Kwang Rok Kim Sung-Hoon Ahn Myung Ae Bae Nam Sook Kang 《Bioorganic & medicinal chemistry letters》2010,20(17):5130-5132
In this work, we tried to find a new scaffold for a CB1 receptor antagonist using virtual screening. We first analyzed structural features for the known cannabinoid-1 receptor antagonists and, then, we built pharmacophore models using the HipHop concept and carried out a docking study based on our homology CB1 receptor 3D structure. The most active compound, including thiazole-4-one moiety, showed an activity value of 125 nM IC50, with a good PK profile. 相似文献
14.
Sieling PA Chung W Duong BT Godowski PJ Modlin RL 《Journal of immunology (Baltimore, Md. : 1950)》2003,170(1):194-200
Bacterial lipopeptides (bLPs) are increasingly used as adjuvants to activate cell-mediated immune responses to foreign Ags. To explore mechanisms whereby bLPs adjuvant T cell responses, we stimulated human PBMCs with bLPs. We found that bLPs stimulate T cells to proliferate and produce IFN-gamma in an accessory cell-dependent manner and in the absence of exogenous protein Ags. The ability of bLPs to stimulate T cell proliferation was Toll-like receptor 2 dependent and required IL-12, interaction with costimulatory molecules, and MHC proteins. Our data suggest that bLPs adjuvant adaptive Th1 responses by enhancing Ag presentation of endogenous peptides. 相似文献
15.
Raoul M Patigny D Fabis F Dauphin F Rault S Sapi J Laronze JY 《Journal of enzyme inhibition and medicinal chemistry》2006,21(3):251-260
Several new 2-vinyl-Nb,Nb-dimethyltryptamines were prepared using Fischer indole synthesis followed by simple functional group transformations and evaluated on 5-HT4, 5-HT5, 5-HT6 and 5-HT7 serotonin receptors. It was found that 2-vinyl substitution conferred a potent and selective 5-HT6 binding activity to these molecules which could be enhanced by Na-arylsulfonyl substituents. 相似文献
16.
Andres CJ Antal Zimanyi I Deshpande MS Iben LG Grant-Young K Mattson GK Zhai W 《Bioorganic & medicinal chemistry letters》2003,13(17):2883-2885
The synthesis of novel ligands for the NPY(2) receptor using solid phase split pool methodology is described. One of the analogues, diamine 16, was found to be a potent NPY(2) binder. 相似文献
17.
Elworthy TR Brill ER Caires CC Kim W Lach LK Tracy JL Chiou SS 《Bioorganic & medicinal chemistry letters》2005,15(10):2523-2526
2-Piperidones were prepared bearing heptanoic acid or a thioether heptanoic acid at the 1-position as well as appropriately substituted at the 6-position to mimic the structure of prostaglandins. The stereochemical purity at the 6-position was determined to be 95% ee for an advanced synthetic intermediate. The 2-piperidones were identified as potent agonists at the EP4 prostanoid receptor. They displayed a high affinity (Ki 5-130 nM) at EP4 and subtype selectivity. 相似文献
18.
Lee-Dutra A Arienti KL Buzard DJ Hack MD Khatuya H Desai PJ Nguyen S Thurmond RL Karlsson L Edwards JP Breitenbucher JG 《Bioorganic & medicinal chemistry letters》2006,16(23):6043-6048
A series of 2-arylbenzimidazoles was synthesized and found to bind with high affinity to the human histamine H(4) receptor. Structure-activity relationships were investigated through library preparation and evaluation as well as traditional medicinal chemistry approaches, leading to the discovery of compounds with single-digit nanomolar affinity for the H(4) receptor. 相似文献
19.
Oscar?Parravicini M.?Lucrecia?Bogado Sebastián?Rojas Emilio?L.?Angelina Sebastián?A.?Andujar Lucas?J.?Gutierrez Nuria?Cabedo M.?Jesús?Sanz M.?Pilar?López-Gresa Diego?Cortes Ricardo?D.?Enriz
A series of tetrahydroisoquinolines functionalized with carbamates is reported here as highly selective ligands on the dopamine D2 receptor. These compounds were selected by means of a molecular modeling study. The studies were carried out in three stages: first an exploratory study was carried out using combined docking techniques and molecular dynamics simulations. According to these results, the bioassays were performed; these experimental studies corroborated the results obtained by molecular modeling. In the last stage of our study, a QTAIM analysis was performed in order to determine the main molecular interactions that stabilize the different ligand-receptor complexes. Our results show that the adequate use of combined simple techniques is a very useful tool to predict the potential affinity of new ligands at dopamine D1 and D2 receptors. In turn the QTAIM studies show that they are very useful to evaluate in detail the molecular interactions that stabilize the different ligand-receptor complexes; such information is crucial for the design of new ligands. 相似文献
20.
Abdel-Aal AB Al-Isae K Zaman M Toth I 《Bioorganic & medicinal chemistry letters》2011,21(19):5863-5865
Stimulation of toll-like receptor 2 (TLR2) by bacterial lipoproteins induces fast non-specific immune responses against pathogens followed by slow but specific adaptive immune responses. Development of synthetic TLR2 agonists/antagonists would be useful in the prevention of different infectious and immunologic disorders. The current study reports synthesis and TLR2 activity of two simple TLR2 ligands, which feature minimal structural requirement for TLR2 activity (two long lipid chains) and stimulate agonistic activity at nanomolar concentration. 相似文献