共查询到20条相似文献,搜索用时 15 毫秒
1.
Design and synthesis of amidino-tyrosine derivatives as non-peptide fibrinogen receptor antagonists.
T L Xu X T Jiang W Y Hua P Z Ni Y M Pei 《Bioorganic & medicinal chemistry letters》1999,9(14):1933-1936
The design, synthesis and antiaggregation activity of amidino-tyrosine derivatives based on Arg-Gly-Asp (RGD) tripeptide sequence as non-peptide fibrinogen receptor antagonists is described. Optimization of the spacer and the substituent at the C-terminal is reported. 相似文献
2.
Zaghdane H Boyd M Colucci J Simard D Berthelette C Leblanc Y Wang Z Houle R Lévesque JF Molinaro C Hamel M Stocco R Sawyer N Sillaots S Gervais F Gallant M 《Bioorganic & medicinal chemistry letters》2011,21(11):3471-3474
A new series of indole amide acting as hCRTH2 receptor ligands had been explored and are described herein. Several amide derivatives displaying low nanomolar activity in hCRTH2 binding and whole blood assays were identified. They were found to behave as a full antagonists, exhibiting good selectivity over related prostaglandin receptors. Also, prototypical compounds in this novel series which displayed acceptable CYP profiles and were orally bioavailable in rats were identified. 相似文献
3.
H S Ahn L Arik G Boykow D A Burnett M A Caplen M Czarniecki M S Domalski C Foster M Manna A W Stamford Y Wu 《Bioorganic & medicinal chemistry letters》1999,9(14):2073-2078
A series of pyrroloquinazolines has been discovered that represent novel small molecule inhibitors of the intramolecular ligand of the thrombin receptor. Analogs were prepared to study the structure-activity relationships of substitution at the N 1, N3, and N7 positions of the heterocycle. Compounds 4e and 4f have been identified with IC50's of 56 and 52 nM, respectively. 相似文献
4.
In this study, a series of novel ethylenediamine compounds were obtained by structural modification of the lead compounds with thonzylamine, and using the principle of modifying by bioisostere formation and modification with alkyl groups. In vitro assay, the biological activities showed that the target compounds have good properties in inhibiting mast cell degranulation and releasing histamine and β-aminohexidase, such as the compounds 5c, 5g, 5k, 5l and 5o, especially of compound 5k to mast cell degranulation is IC50 = 0.0106 ± 0.001 μmol?L?1, histamine release was IC50 = 0.0192 ± 0.005 μmol?L?1 and β-hexosaminidase release was IC50 = 0.0455 ± 0.002 μmol?L?1 in vitro. At the same time, in vivo biological activities assay results showed that have a good Histamie induce bronchospasm effect with relatively long duration and good protective effect in vivo, among which the protective effect of compound 5k was 79.74 ± 0.30%, compounds 5c, 5g, 5k, 5l and 5o could inhibit the capillary permeability of increasing which were caused by histamine. 相似文献
5.
Yamamoto S Matsunaga N Hitaka T Yamada M Hara T Miyazaki J Santou T Kusaka M Yamaoka M Kanzaki N Furuya S Tasaka A Hamamura K Ito M 《Bioorganic & medicinal chemistry》2012,20(1):422-434
A series of 4-phenylpyrrole derivatives D were designed, synthesized, and evaluated for their potential as novel orally available androgen receptor antagonists therapeutically effective against castration-resistant prostate cancers. 4-Phenylpyrrole compound 1 exhibited androgen receptor (AR) antagonistic activity against T877A and W741C mutant-type ARs as well as wild-type AR. An arylmethyl group incorporated into compound 1 contributed to enhancement of antagonistic activity. Compound 4n, 1-{[6-chloro-5-(hydroxymethyl)pyridin-3-yl]methyl}-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile exhibited inhibitory effects on tumor cell growth against the bicalutamide-resistant LNCaP-cxD2 cell line as well as the androgen receptor-dependent JDCaP cell line in a mouse xenograft model. These results demonstrate that this series of pyrrole compounds are novel androgen receptor antagonists with efficacy against prostate cancer cells, including castration-resistant prostate cancers such as bicalutamide-resistant prostate cancer. 相似文献
6.
Johnson SG Gunnet JW Moore JB Miller W Wines P Rivero RA Combs D Demarest KT 《Bioorganic & medicinal chemistry letters》2006,16(13):3362-3366
A series of 1,3-disubstituted cyclohexylmethyl urea and amide derivatives were synthesized as motilin receptor antagonists. Starting from known motilin antagonists, 1a and 1b, the cyclopentene scaffold was replaced and the four recognition elements optimized to arrive at a potent novel series. 相似文献
7.
Li G Zhou H Jiang Y Keim H Topiol SW Poda SB Ren Y Chandrasena G Doller D 《Bioorganic & medicinal chemistry letters》2011,21(4):1236-1242
Two series of 4-arylpiperidinyl amide and N-arylpiperdin-3-yl-cyclopropane carboxamide derivatives exhibiting diverse functionality at rat MT1 and MT2 receptors are reported. Compounds 11f and 18b (MT1/MT2 agonist) have human microsomal intrinsic clearance comparable to ramelteon. 相似文献
8.
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
9.
Palani A Dugar S Clader JW Greenlee WJ Ruperto V Duffy RA Lachowicz JE 《Bioorganic & medicinal chemistry letters》2004,14(7):1791-1794
Low molecular weight amide derivatives were synthesized and evaluated as M(2) receptor antagonists for the treatment of Alzheimer's disease. Isopropyl amides 19 and 31 are highly potent, selective and low molecular weight M(2) receptor antagonists with structural features different from our clinical candidate 1. 相似文献
10.
《Bioorganic & medicinal chemistry letters》2019,29(15):1974-1980
A novel series of indazole/indole derivatives were discovered as glucagon receptor (GCGR) antagonists through scaffold hopping based on two literature leads: MK-0893 and LY-2409021. Further structure-activity relationship (SAR) exploration and optimization led to the discovery of multiple potent GCGR antagonists with excellent pharmacokinetic properties in mice and rats, including low systemic clearance, long elimination half-life, and good oral bioavailability. These potent GCGR antagonists could be used for potential treatment of type II diabetes. 相似文献
11.
Nishikawa-Shimono R Sekiguchi Y Koami T Kawamura M Wakasugi D Watanabe K Wakahara S Matsumoto K Takayama T 《Bioorganic & medicinal chemistry letters》2012,22(9):3305-3310
Synthesis and structure-activity relationship of a novel series of isoquinoline CRTH2 receptor antagonists are described. One of the most potent compounds, TASP0376377 (6m), showed not only potent binding affinity (IC(50)=19 nM) but also excellent functional antagonist activity (IC(50)=13 nM). TASP0376377 was tested for its ability of a chemotaxis assay to show the effectiveness (IC(50)=23 nM), which was in good agreement with the CRTH2 antagonist potency. Furthermore, TASP0376377 showed sufficient selectivity for binding to CRTH2 over the DP1 prostanoid receptor (IC(50)>1 μM) and COX-1 and COX-2 enzymes (IC(50)>10 μM). 相似文献
12.
Chelliah MV Chackalamannil S Xia Y Eagen K Greenlee WJ Ahn HS Agans-Fantuzzi J Boykow G Hsieh Y Bryant M Chan TM Chintala M 《Bioorganic & medicinal chemistry letters》2012,22(7):2544-2549
Discovery of a novel nor-seco himbacine analog as potent thrombin receptor (PAR-1) antagonist is described. Despite low plasma level, these new analogs showed excellent ex vivo efficacy in the monkey platelet aggregation assay. A potent hydroxy metabolite generated in vivo was identified as the agent responsible for the ex vivo efficacy. Following this discovery, the metabolite series was optimized to obtain analogs that showed very good ex vivo efficacy along with excellent pharmacokinetic profile in c. monkey. 相似文献
13.
Zhang C Westaway SM Speake JD Bishop MJ Goetz AS Carballo LH Hu M Epperly AH 《Bioorganic & medicinal chemistry letters》2011,21(2):670-676
Opioid receptors play an important role in both behavioral and homeostatic functions. We herein report tetrahydroquinoline derivatives as opioid receptor antagonists. SAR studies led to the identification of the potent antagonist 2v, endowed with 1.58 nM (Ki) functional activity against the μ opioid receptor. DMPK data suggest that novel tetrahydroquinoline analogs may be advantageous in peripheral applications. 相似文献
14.
Westaway SM Thompson M Rami HK Stemp G Trouw LS Mitchell DJ Seal JT Medhurst SJ Lappin SC Biggs J Wright J Arpino S Jerman JC Cryan JE Holland V Winborn KY Coleman T Stevens AJ Davis JB Gunthorpe MJ 《Bioorganic & medicinal chemistry letters》2008,18(20):5609-5613
6-Phenylnicotinamide (2) was previously identified as a potent TRPV1 antagonist with activity in an in vivo model of inflammatory pain. Optimization of this lead through modification of both the biaryl and heteroaryl components has resulted in the discovery of 6-(4-fluorophenyl)-2-methyl-N-(2-methylbenzothiazol-5-yl)nicotinamide (32; SB-782443) which possesses an excellent overall profile and has been progressed into pre-clinical development. 相似文献
15.
Kurukulasuriya R Sorensen BK Link JT Patel JR Jae HS Winn MX Rohde JR Grihalde ND Lin CW Ogiela CA Adler AL Collins CA 《Bioorganic & medicinal chemistry letters》2004,14(9):2047-2050
Biaryl amides derived from a reported series of ureas 1 were evaluated and found to be potent human glucagon receptor antagonists. The benzofuran analogue 6i was administered in Sprague-Dawley rats and blocked the effects of an exogenous glucagon challenge. 相似文献
16.
Li Tang Liying Zhao Lingjuan Hong Fenyan Yang Rong Sheng Jianzhong Chen Ying Shi Naimin Zhou Yongzhou Hu 《Bioorganic & medicinal chemistry》2013,21(19):5936-5944
A series of novel 3-substituted-indole derivatives with a benzyl tertiary amino moiety were designed, synthesized and evaluated as H3 receptor antagonists and free radical scavengers for Alzheimer’s disease therapy. Most of these synthesized compounds exhibited moderate to potent antagonistic activities in CREs driven luciferase assay. In particular, compound 2d demonstrated the most favorable H3 receptor antagonistic activity with the IC50 value of 0.049 μM. Besides, it also displayed high binding affinity to H3 receptor (Ki = 4.26 ± 2.55 nM) and high selectivity over other three histamine receptors. Moreover, 2d and other two 3-substituted indole derivatives 1d and 3d exerted potent ABTS radical cation scavenging capacities similar to melatonin. Above results illustrate that 2d is an interesting lead for extensive optimization to explore new drug candidate for AD therapy. 相似文献
17.
Sendzik M Janc JW Cabuslay R Honigberg L Mackman RL Magill C Squires N Waldeck N 《Bioorganic & medicinal chemistry letters》2004,14(12):3181-3184
The rational design and synthesis of beta-amino-alpha-hydroxy amide derivatives as reversible inhibitors of methionine aminopeptidase-2 (MetAP2) with anti-proliferative activity against human umbilical vein endothelial cells (HUVECs) is described. 相似文献
18.
Rie Nishikawa-Shimono Yoshinori Sekiguchi Takeshi Koami Madoka Kawamura Daisuke Wakasugi Kazuhito Watanabe Shunichi Wakahara Kayo Kimura Susumu Yamanobe Tetsuo Takayama 《Bioorganic & medicinal chemistry》2013,21(24):7674-7685
In this study, we describe the synthesis and structure–activity relationship (SAR) of a series of isoquinoline chemoattractant receptor–homologous molecule expressed on Th2 cells (CRTH2) antagonists. TASP0376377 (15-20), one of the most potent compounds, showed a potent binding affinity (IC50 = 19 nM) in addition to the excellent functional antagonist activity (IC50 = 13 nM). Moreover, the efficacy of this compound in a chemotaxis assay (IC50 = 23 nM) was in good agreement with its potency as a CRTH2 antagonist. In addition, 15-20 exhibited greater selectivity in binding to CRTH2 than to the DP1 prostanoid receptor (IC50 >1 μM) or the enzymes COX-1 and COX-2 (IC50 >10 μM). 相似文献
19.
Ting PC Lee JF Wu J Umland SP Aslanian R Cao J Dong Y Garlisi CG Gilbert EJ Huang Y Jakway J Kelly J Liu Z McCombie S Shah H Tian F Wan Y Shih NY 《Bioorganic & medicinal chemistry letters》2005,15(5):1375-1378
Bipiperidine amide 1 has been identified as a CC chemokine receptor 3 (CCR3) antagonist. Optimization of its structure-activity relationship has resulted in the identification of cis (R,R)-4-[(3,4-dichlorophenyl)methyl]-3-hydroxymethyl-1'(6-quinolinylcarbonyl)-1,4'-bipiperidine 14n, which exhibits potent receptor affinity and inhibition of both calcium flux and eosinophil chemotaxis. 相似文献
20.
Guo Li Lindsey C.K. Aschenbach Hengjun He Dana E. Selley Yan Zhang 《Bioorganic & medicinal chemistry letters》2009,19(6):1825-1829
Mu opioid receptor antagonists have clinical utility and are important research tools. To develop non-peptide and highly selective mu opioid receptor antagonist, a series of 14-O-heterocyclic-substituted naltrexone derivatives were designed, synthesized, and evaluated. These compounds showed subnanomolar-to-nanomolar binding affinity for the mu opioid receptor. Among them, compound 1 exhibited the highest selectivity for the mu opioid receptor over the delta and kappa receptors. These results implicated an alternative ‘address’ domain in the extracellular loops of the mu opioid receptor. 相似文献