共查询到20条相似文献,搜索用时 0 毫秒
1.
Ksander GM Shetty SS DelGrande D Balwierczak JL Bruseo CW Savage P deJesus R Yuan A Webb RL Jeng AY 《Canadian journal of physiology and pharmacology》2002,80(5):464-469
Endothelin-1 (ET-1) is a potent mitogen and modulator of vascular tone. It is synthesized and released from endothelial cells and acts upon two receptor subtypes designated as ETA and ETB. In this study, a series of potent dipeptide sulfonamide dual-endothelin ETA/ETB receptor antagonists were prepared to investigate their potential benefit in vascular diseases. CGS 31398 inhibited [125I]ET-1 binding to human ETA and ETB receptors expressed in Chinese hamster ovary (CHO) cells (ETA/CHO, ETB/CHO) with respective IC50 values of 0.26 and 0.12 nM. However, in anesthetized rats, this compound markedly potentiated ET-1-induced renal vascular resistance, a response normally observed with selective ETB receptor antagonists. To determine whether species differences account for these results, a direct comparison was made between binding to rat and rabbit aortic membranes versus functional antagonism in isolated rat aortic rings. It was found that CGS 31398 had potent affinity for the ETA receptor in rat and rabbit aorta with IC50 values of 0.87 and 0.79 nM, respectively. Inhibition of ET-1-induced contractions of rat aorta by the compound was considerably weaker than expected (pKB = 6.4), while that of sarafotoxin S6c induced contraction of dog saphenous vein (100% inhibition at 100 nM) was consistent with corresponding binding data. These results suggest that although CGS 31398 is a potent dual inhibitor of ETA/ETB receptor binding, it surprisingly displays potent ETB and weak ETA receptor antagonism in functional assays. 相似文献
2.
Biological profiles of highly potent novel endothelin antagonists selective for the ETA receptor. 总被引:39,自引:0,他引:39
M Ihara K Noguchi T Saeki T Fukuroda S Tsuchida S Kimura T Fukami K Ishikawa M Nishikibe M Yano 《Life sciences》1992,50(4):247-255
We describe novel potent endothelin (ET) antagonists that are highly potent and selective for the ETA receptor (selective to ET-1). Of the synthetic analogs based on ETA antagonist BE-18257A isolated from Streptomyces misakiensis (IC50 value for ETA receptor on porcine aortic smooth muscle cells (VSMCs); 1.4 microM), the compounds BQ-123 and BQ-153 greatly improved the binding affinity of [125I]ET-1 for ETA receptors on VSMCs (IC50; 7.3 and 8.6 nM, respectively), whereas they barely inhibited [125I]ET-1 binding to ETB receptors (nonselective with respect to isopeptides of ET family) in the cerebellar membranes (IC50; 18 and 54 microM, respectively). Associated with the increased affinity for ETA receptors, these peptides antagonized ET-1-induced constriction of isolated porcine coronary artery. However, there was a small amount of ET-1-induced vasoconstriction resistant to these antagonists, which paralleled the incomplete inhibition of [125I]ET-1 binding in the membrane of the aortic smooth muscle layer. These data suggest that the artery has both ETA and ETB receptors responsible for ET-1-induced vasoconstriction. The antagonists shifted the concentration-response curve to the right for ET-1 in the coronary artery, and increased the apparent dissociation constant in the Scatchard analysis of [125I]ET-1 binding on the VSMCs without affecting the binding capacity, indicative of the competitive antagonism for ETA receptor. In conscious rats, pretreatment with the antagonists markedly antagonized ET-1-induced sustained pressor responses in dose-dependent fashion without affecting ET-1-induced transient depressor action, suggesting that the pressor action is mediated by ETA receptors, while the depressor action is mediated by ETB receptors. In addition, pretreatment with the potent antagonists prevented ET-1-induced sudden death in mice. Thus, these potent ETA antagonists should provide a powerful tool for exploring the therapeutic uses of ETA antagonists in putative ET-1-related disorders. 相似文献
3.
X Jiao DJ Kopecky B Fisher DE Piper M Labelle S McKendry M Harrison S Jones J Jaen AK Shiau P Escaron J Danao A Chai P Coward F Kayser 《Bioorganic & medicinal chemistry letters》2012,22(18):5966-5970
The present report describes our efforts to convert an existing LXR agonist into an LXR antagonist using a structure-based approach. A series of benzenesulfonamides was synthesized based on structural modification of a known LXR agonist and was determined to be potent dual liver X receptor (LXR α/β) ligands. Herein we report the identification of compound 54 as the first reported LXR antagonist that is suitable for pharmacological in vivo evaluation in rodents. 相似文献
4.
Novel peptide-based endothelin (ET) receptor antagonists were designed and synthesized in our laboratory. BQ-485, HIM-CO-Leu-d-Trp-d-Trp-OH, was selected as the leading compound. The primary structures of these new tripeptides were ABO-CO-Leu-d-Trp-d-AA(X)-OH. The introduction of unnatural aromatic amino acids into these tripeptides was useful in the structure-activity relationship studies. Among the 20 tripeptides, 16 of them showed high activities against the contraction of rat aortic smooth muscles induced by ET-1. 相似文献
5.
Allan AC Billinton A Brown SH Chowdhury A Eatherton AJ Fieldhouse C Giblin GM Goldsmith P Hall A Hurst DN Naylor A Rawlings DA Sime M Scoccitti T Theobald PJ 《Bioorganic & medicinal chemistry letters》2011,21(14):4343-4348
We describe the discovery and optimization of a novel series of benzofuran EP1 antagonists, leading to the identification of 26d, a novel nonacidic EP1 antagonist which demonstrated efficacy in preclinical models of chronic inflammatory pain. 相似文献
6.
《Bioorganic & medicinal chemistry》2016,24(19):4675-4691
A promising lead compound 1 of a benzimidazole series has been identified as a corticotropin-releasing factor 1 (CRF1) receptor antagonist. In this study, we focused on replacement of a 7-alkylamino group of 1, predicted to occupy a large lipophilic pocket of a CRF1 receptor, with an aryl group. During the course of this examination, we established new synthetic approaches to 2,7-diarylaminobenzimidazoles. The novel synthesis of 7-arylaminobenzimidazoles culminated in the identification of compounds exhibiting inhibitory activities comparable to the alkyl analog 1. A representative compound, p-methoxyanilino analog 16g, showed potent CRF binding inhibitory activity against a human CRF1 receptor and human CRF1 receptor antagonistic activity (IC50 = 27 nM, 56 nM, respectively). This compound exhibited ex vivo 125I-Tyr0 (125I-CRF) binding inhibitory activity in mouse frontal cortex, olfactory bulb, and pituitary gland at 20 mg/kg after oral administration. In this report, we discuss the structure–activity-relationship of these 7-arylamino-1H-benzimidazoles and their synthetic method. 相似文献
7.
C Cyr K Huebner T Druck R Kris 《Biochemical and biophysical research communications》1991,181(1):184-190
A cDNA clone encoding a human endothelin receptor was isolated from a placenta cDNA library. The deduced amino acid sequence of the clone is 94% identical to the bovine endothelin ETA receptor and represents the human homologue. The human endothelin ETA receptor gene was localized to chromosome 4 by analysis of its segregation pattern in rodent-human hybrids. 相似文献
8.
Dasgupta F Gangadhar N Bruhaspathy M Verma AK Sarin S Mukherjee AK 《Bioorganic & medicinal chemistry letters》2001,11(4):555-557
A series of new peptoids as endothelin receptor antagonists has been synthesized. Screening them for their ability to bind with endothelin receptors (ET(A) and ET(B)) competitively in the presence of (125I) endothelin led to the discovery of compounds as possible leads with IC50s in the low micromolar concentrations. 相似文献
9.
Firooznia F Cheung AW Brinkman J Grimsby J Gubler ML Hamid R Marcopulos N Ramsey G Tan J Wen Y Sarabu R 《Bioorganic & medicinal chemistry letters》2011,21(7):1933-1936
The highly potent but modestly selective N-(2-amino-4-methoxy-benzothiazol-7-yl)-N-ethyl-acetamide derivative 2 was selected as the starting point for the design of novel selective A2B antagonists, due to its excellent potency, and good drug-like properties. A series of compounds containing nonaromatic amides or ureas of five- or six-membered rings, and also bearing an m-trifluoromethyl-phenyl group (shown to impart superior potency) was prepared and evaluated for their selectivity against the A2A and A1 receptors. This work resulted in the identification of compound 30, with excellent potency and high selectivity against both A2A and A1 receptors. 相似文献
10.
Bis-sulfonamides as endothelin receptor antagonists 总被引:2,自引:0,他引:2
Boss C Bolli MH Weller T Fischli W Clozel M 《Bioorganic & medicinal chemistry letters》2003,13(5):951-954
Modification of the structure of bosentan 1, the first marketed endothelin receptor antagonist (Tracleer), by introduction of a second sulfonamide function at the alkoxy side chain, led to bis-sulfonamides 2. This allowed to prepare dual ET(A)/ET(B) as well as ET(B) receptor selective antagonists, which could serve as tools to investigate the pharmacological consequences of selective ET(B) receptor blockade. 相似文献
11.
Hall A Billinton A Brown SH Chowdhury A Giblin GM Goldsmith P Hurst DN Naylor A Patel S Scoccitti T Theobald PJ 《Bioorganic & medicinal chemistry letters》2008,18(8):2684-2690
We describe the medicinal chemistry approach that generated a novel indole series of EP(1) receptor antagonists. The SAR of this new template was evaluated and culminated in the identification of compound 12g which demonstrated in vivo efficacy in a preclinical model of inflammatory pain. 相似文献
12.
Lange UE Braje WM Amberg W Kettschau G 《Bioorganic & medicinal chemistry letters》2003,13(10):1721-1724
A new solid-phase synthesis for ET receptor antagonists suitable for automation is presented. A support bound 2-hydroxybutyric acid derivative was converted to the corresponding ether derivatives using 4-halo-2-methylsulfonylpyrimidines. Subsequent Suzuki coupling with various aryl boronic acids gave the desired antagonists in good yields and purities. Highly potent antagonists with excellent selectivity for ET(A) were obtained. 相似文献
13.
Stefano Crosignani Marc Missotten Christophe Cleva Ruggero Dondi Yann Ratinaud Yves Humbert Ashis Baran Mandal Agnès Bombrun Christine Power André Chollet Amanda Proudfoot 《Bioorganic & medicinal chemistry letters》2010,20(12):3614-3617
The discovery of a novel series of CXCR3 antagonists is described. Starting from an HTS positive, iterative optimization gave potent compounds (IC50 15 nM in a chemotaxis assay). The strategy employed to improve the metabolic stability of these derivatives is described. 相似文献
14.
Mihalic JT Chen X Fan P Chen X Fu Y Liang L Reed M Tang L Chen JL Jaen J Li L Dai K 《Bioorganic & medicinal chemistry letters》2011,21(23):7001-7005
A new class of MCHR1 antagonists was discovered via a high-throughput screen. Optimization of the lead structure resulted in the identification of indole 10e. This compound possesses good pharmacokinetic properties across preclinical species and is efficacious in reducing food consumption in an MCH cannulated rat model and a cynomolgus monkey food consumption model. 相似文献
15.
Yves Leblanc Patrick Roy Claude Dufresne Nicolas Lachance Zhaoyin Wang Gary O’Neill Gillian Greig Danielle Denis Marie-Claude Mathieu Deborah Slipetz Nicole Sawyer Nancy Tsou 《Bioorganic & medicinal chemistry letters》2009,19(8):2125-2128
Azaindole based structures were evaluated as DP1 receptor antagonists. This work has lead to the discovery of potent, selective and distinct DP1 receptor antagonists. 相似文献
16.
Marna Pippel Brett D. Allison Victor K. Phuong Lina Li Magda F. Morton Clodagh Prendergast Xiaodong Wu Nigel P. Shankley Michael H. Rabinowitz 《Bioorganic & medicinal chemistry letters》2009,19(22):6373-6375
A series of CCK2R-selective anthranilic amides is shown to derive CCK1R affinity via selective substitution of the amide side chain. Thus, extending the length of the original benzamide side chain by a single methylene unit imparts CCK1R affinity to the series, and further fine tuning of the affinity results in CCK1R selectivity of greater than 100-fold. 相似文献
17.
Clasby MC Chackalamannil S Czarniecki M Doller D Eagen K Greenlee WJ Lin Y Tsai H Xia Y Ahn HS Agans-Fantuzzi J Boykow G Chintala M Foster C Bryant M Lau J 《Bioorganic & medicinal chemistry letters》2006,16(6):1544-1548
The design, synthesis, and SAR studies of a structurally novel series of highly potent thrombin receptor (PAR-1) antagonists are described. Compound 30 is a highly potent thrombin receptor antagonist (IC(50)=6.3 nM), a related compound 36 showing efficacy in a monkey ex vivo study. 相似文献
18.
Qian W Chen JJ Human J Aya T Zhu J Biswas K Peterkin T Hungate RW Arik L Johnson E Kumar G Joseph S Jona J Guo HX Wu Z 《Bioorganic & medicinal chemistry letters》2012,22(2):1061-1067
In a series of bradykinin B1 antagonists, we discovered that replacement of oxopiperazine acetamides with dehydro-oxopiperazine acetamides provided compounds with enhanced activity against the B1 receptor. The synthesis and SAR leading to potent analogs with reduced molecular weight will be discussed. 相似文献
19.
Mihalic JT Kim YJ Lizarzaburu M Chen X Deignan J Wanska M Yu M Fu J Chen X Zhang A Connors R Liang L Lindstrom M Ma J Tang L Dai K Li L 《Bioorganic & medicinal chemistry letters》2012,22(5):2046-2051
A series of benzodiazepine antagonists of the human ghrelin receptor GHSR1a were synthesized and their antagonism and metabolic stability were evaluated. The potency of these analogs was determined using a functional aequorin (Euroscreen) luminescent assay measuring the intracellular Ca(2+) concentration, and their metabolic stability was measured using an in vitro rat and human S9 hepatocyte assay. These efforts led to the discovery of a potent ghrelin antagonist with good rat pharmacokinetic properties. 相似文献
20.
M Ihara T Fukuroda T Saeki M Nishikibe K Kojiri H Suda M Yano 《Biochemical and biophysical research communications》1991,178(1):132-137
A competitive endothelin (ET) antagonist, BE-18257B, was isolated from the fermentation products of Streptomyces misakiensis. It is a novel cyclic pentapeptide, cyclo(-D-Glu-L-Ala-allo-D-Ile-L-Leu-D-Trp-), and binds to ETA receptors (ET-1 selective) in cardiovascular tissues, but not to ETB receptors (equally sensitive to isopeptides of ET family) in kidney, adrenal gland and cerebellum tissues. BE-18257B also antagonizes ET-1-induced vasoconstriction in rabbit iliac artery and pressor action in rats. Thus it is a selective ETA antagonist and should provide a valuable tool for elucidation of the pharmacological and pathophysiological roles of ET-1. 相似文献