共查询到20条相似文献,搜索用时 46 毫秒
1.
McGuinness BF Ho KK Stauffer TM Rokosz LL Mannava N Kultgen SG Saionz K Klon A Chen W Desai H Rogers WL Webb M Yin J Jiang Y Li T Yan H Jing K Zhang S Majumdar KK Srivastava V Saha S 《Bioorganic & medicinal chemistry letters》2010,20(24):7414-7420
A novel series of quinolinone-based adenosine A(2B) receptor antagonists was identified via high throughput screening of an encoded combinatorial compound collection. Synthesis and assay of a series of analogs highlighted essential structural features of the initial hit. Optimization resulted in an A(2B) antagonist (2i) which exhibited potent activity in a cAMP accumulation assay (5.1 nM) and an IL-8 release assay (0.4 nM). 相似文献
2.
McCort G Hoornaert C Aletru M Denys C Duclos O Cadilhac C Guilpain E Dellac G Janiak P Galzin AM Delahaye M Guilbert F O'Connor S 《Bioorganic & medicinal chemistry》2001,9(8):2129-2137
Quinolin-2-ones bearing a heteroaryl-piperazine linked by a two carbon chain at the 3- or 4-position were synthesised and evaluated as mixed 5-HT(1B)/5-HT(2A) receptor antagonists. Potent mixed antagonists were obtained with thieno[3,2-c]pyridine derivatives. In this series, compound 2.1 (SL 65.0472) proved to be functional antagonist at both the 5-HT(2A) receptor (rat in vivo 5-HT-induced hypertension model) and the 5-HT(1B) receptor (dog in vitro saphenous vein assay). 相似文献
3.
The antagonist actions of three sub-series of tetrahydro-beta-carbolines at the serotonin 2B (5HT2B) contractile receptor in the rat stomach fundus are analyzed in relation to the physicochemical properties of the molecules. Significant correlations are obtained between the 5HT2B receptor antagonist affinity and the hydrophobic, steric, electronic, hydrogen bond acceptor and some indicator variables of substituents. Based on these findings, the mode of actions of these congeneric series and future strategy to synthesize more potential compounds are discussed. 相似文献
4.
The antagonist actions of three sub-series of tetrahydro- β -carbolines at the serotonin 2B (5HT 2B) contractile receptor in the rat stomach fundus are analyzed in relation to the physicochemical properties of the molecules. Significant correlations are obtained between the 5HT 2B receptor antagonist affinity and the hydrophobic, steric, electronic, hydrogen bond acceptor and some indicator variables of substituents. Based on these findings, the mode of actions of these congeneric series and future strategy to synthesize more potential compounds are discussed. 相似文献
5.
Tabrizi MA Baraldi PG Preti D Romagnoli R Saponaro G Baraldi S Moorman AR Zaid AN Varani K Borea PA 《Bioorganic & medicinal chemistry》2008,16(5):2419-2430
A new series of 1,3-dipropyl-8-(1-phenylacetamide-1H-pyrazol-3-yl)-xanthine derivatives has been identified as potent A(2B) adenosine receptor antagonists. The products have been evaluated for their binding affinities for the human A(2B), A(1), A(2A), and A(3) adenosine receptors. N-(4-chloro-phenyl)-2-[3-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl] (11c) showed a high affinity for the human A(2B) adenosine receptor K(i)=7nM and good selectivity (A(1), A(2A), A(3)/A(2B)>140). Synthesis and SAR of this novel class of compounds is presented herein. 相似文献
6.
Quinazolines as adenosine receptor antagonists: SAR and selectivity for A2B receptors 总被引:1,自引:0,他引:1
Webb TR Lvovskiy D Kim SA Ji Xd Melman N Linden J Jacobson KA 《Bioorganic & medicinal chemistry》2003,11(1):77-85
We have recently reported the discovery of numerous new compounds that are selective inhibitors of all of the subtypes of the adenosine receptor family via a pharmacophore database searching and screening strategy. During the course of this work we made the unexpected discovery of a potent A(2B) receptor antagonist, 4-methyl-7-methoxyquinazolyl-2-(2'-amino-4'-imidazolinone) (38, CMB 6446), which showed selectivity for this receptor and functioned as an antagonist, with a binding K(i) value of 112 nM. We explored the effects of both substituent- and ring-structural variations on the receptor affinity in this series of derivatives, which were found to be mostly non-selective adenosine receptor ligands with K(i) values in the micromolar range. Since no enhancement of A(2B) receptor affinity of 38 was achieved, the previously reported pharmacophore-based searching strategy yielded the most potent and selective structurally-related hit in the database originally searched. 相似文献
7.
Lenzi O Colotta V Catarzi D Varano F Squarcialupi L Filacchioni G Varani K Vincenzi F Borea PA Ben DD Lambertucci C Cristalli G 《Bioorganic & medicinal chemistry》2011,19(12):3757-3768
This paper reports the study of new 2-phenyl- and 2-methylpyrazolo[3,4-c]quinolin-4-ones (series A) and 4-amines (series B), designed as adenosine receptor (AR) antagonists. The synthesized compounds bear at the 6-position various groups, with different lipophilicity and steric hindrance, that were thought to increase human A(1) and A(2A) AR affinities and selectivities, with respect to those of the parent 6-unsubstituted compounds. In series A, this modification was not tolerated since it reduced AR affinity, while in series B it shifted the binding towards the hA(1) subtype. To rationalize the observed structure-affinity relationships, molecular docking studies at A(2A)AR-based homology models of the A(1) and A(3) ARs and at the A(2A)AR crystal structure were carried out. 相似文献
8.
1-Benzyloxy-4,5-dihydro-1H-imidazol-2-yl-amines,a novel class of NR1/2B subtype selective NMDA receptor antagonists 总被引:1,自引:0,他引:1
Alanine A Bourson A Büttelmann B Gill R Heitz MP Mutel V Pinard E Trube G Wyler R 《Bioorganic & medicinal chemistry letters》2003,13(19):3155-3159
Screening of the Roche compound depository led to the identification of (1-benzyloxy-4,5-dihydro-1H-imidazol-2-yl)-butyl amine 4, a structurally novel NR1/2B subtype selective NMDA receptor antagonist. The structure-activity relationships developed in this series resulted in the discovery of a novel class of potent and selective NMDA receptor blockers displaying activity in vivo. 相似文献
9.
Büttelmann B Alanine A Bourson A Gill R Heitz MP Mutel V Pinard E Trube G Wyler R 《Bioorganic & medicinal chemistry letters》2003,13(10):1759-1762
A series of 4-(3,4-dihydro-1H-isoquinolin-2yl)-pyridines and analogous quinolines was prepared and evaluated as NR1/2B subtype selective NMDA receptor antagonists. 2-Hydroxyalkylamino substitution combines high affinity with selectivity (vs alpha1 and M1 receptors) and activity in vivo. 相似文献
10.
Gregory TF Wright JL Wise LD Meltzer LT Serpa KA Konkoy CS Whittemore ER Woodward RM 《Bioorganic & medicinal chemistry letters》2000,10(6):527-529
A series of 1-(heteroarylthioalkyl)-4-benzylpiperidines was rapidly synthesized through the use of parallel synthesis to investigate the binding affinity for the NR1A/2B receptor subtype. 相似文献
11.
Smith BM Smith JM Tsai JH Schultz JA Gilson CA Estrada SA Chen RR Park DM Prieto EB Gallardo CS Sengupta D Thomsen WJ Saldana HR Whelan KT Menzaghi F Webb RR Beeley NR 《Bioorganic & medicinal chemistry letters》2005,15(5):1467-1470
We report on the synthesis, biological evaluation and structure-activity relationships for a series of 3-benzazepine derivatives as 5-HT(2C) receptor agonists. The compounds were evaluated in functional assays measuring [3H] phosphoinositol turnover in HEK-293 cells transiently transfected with h5-HT(2C), h5-HT(2A) or h5-HT(2B) receptors. Several compounds are shown to be potent and selective 5-HT(2C) receptor agonists, which decrease food intake in a rat feeding model. 相似文献
12.
Meng CQ Rakhit S Lee DK Kamboj R McCallum KL Mazzocco L Dyne K Slassi A 《Bioorganic & medicinal chemistry letters》2000,10(9):903-905
A series of 5-(2- or 3-thienyl)tryptamine derivatives (9) has been synthesized and shown to be potent and selective 5-HT1D versus 5-HT1B receptor agonists and, therefore, potential treatments for migraine. 相似文献
13.
Bienaymé H Chêne L Grisoni S Grondin A Kaloun el-B Poigny S Rahali H Tam E 《Bioorganic & medicinal chemistry letters》2006,16(18):4830-4833
A functional screening highlighted a series of spiro-piperidines as 5-HT2B receptor antagonists. Preliminary structure-activity relationship has been explored driving to potent antagonists (IC50 = 1 nM) and indicating directions for further explorations. 相似文献
14.
Esteve C Nueda A Díaz JL Beleta J Cárdenas A Lozoya E Cadavid MI Loza MI Ryder H Vidal B 《Bioorganic & medicinal chemistry letters》2006,16(14):3642-3645
A new series of 4-(1,3-dialkyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl)benzenesulfonamides has been identified as potent A2B adenosine receptor antagonists. The products have been evaluated for their binding affinities for the human A2B, A1 and A3 adenosine receptors. 6-(4-{[4-(4-Bromobenzyl)piperazin-1-yl]sulfonyl}phenyl)-1,3-dimethyl-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-dione (16) showed a high affinity for the A2B adenosine receptor (IC50=1 nM) and selectivity (A1: 183x; A3: 12660x). Synthesis and SAR of this novel class of compounds showing improved absorption properties is presented herein. 相似文献
15.
Guo Q Chandrasekhar J Ihle D Wustrow DJ Chenard BL Krause JE Hutchison A Alderman D Cheng C Cortright D Broom D Kershaw MT Simmermacher-Mayer J Peng Y Hodgetts KJ 《Bioorganic & medicinal chemistry letters》2008,18(18):5027-5031
The design, synthesis, and structure-activity studies of a novel series of BK B(1) receptor antagonists based on a 1-benzylbenzimidazole chemotype are described. A number of compounds, for example, 38g, with excellent affinity for the cynomolgus macaque and rat bradykinin B(1) receptor were discovered. 相似文献
16.
E S Monteagudo F Calvani F Catrambone C I Fincham A Madami S Meini R Terracciano 《Journal of peptide science》2001,7(5):270-283
We have designed and synthesized a conformationally homogeneous series of cyclic pentapeptides of the general structure c[Pro-aa(i)-D-Tic-Oic-aa(i + 3)] which adopt a type-II' beta-turn conformation believed important for high affinity antagonism of the bradykinin (BK) B2 receptor. We incorporated D-Tic and octahydroindole-2-carboxylic acid (Oic) residues (present in known active antagonists) in a cyclic pentapeptide that would place the D-aa in the i + 1 position of the beta-turn and a proline as a bridge between the C- and N-termini sides of the turn. In positions i and i + 3 alkyl, aromatic, polar or charged amino acids could be introduced without dramatically changing the overall structure. Ten analogues were studied using 1H nuclear magnetic resonance (NMR) and evaluated for their binding affinity for the human B2 receptor. The NMR data in dimethylsulfoxide (DMSO) confirmed the structural homogeneity within the class and, on the basis of this, one representative member of the series was chosen for a detailed structure determination using NMR data in sodium dodecylsulphate (SDS) micelles and molecular dynamics calculations. Despite the structural similarity, the binding affinity of the ten analogues was strongly influenced by the nature of the side-chains in positions i and i + 3, with the doubly charged analogue 49 (pKi = 6.2) proving best. This compound may serve as the starting point for the discovery of new non-peptide bradykinin B2 receptor antagonists. 相似文献
17.
Mederski WW Osswald M Dorsch D Christadler M Schmitges CJ Wilm C 《Bioorganic & medicinal chemistry letters》1999,9(4):619-622
The discovery, synthesis and structure-activity relationships of a series of novel benzofuro[3,2-b]pyridines as non-selective endothelin ET(A)/ET(B) as well as selective ET(B) receptor antagonists are described. The most potent non-selective inhibitor 7s displayed an IC50 of 21 nM and 41 nM for ET(A) and ET(B) receptors, respectively, whereas 7ee merely showed affinity for the ET(B) receptor (IC50 = 3.6 nM). 相似文献
18.
Atkinson PJ Bromidge SM Duxon MS Gaster LM Hadley MS Hammond B Johnson CN Middlemiss DN North SE Price GW Rami HK Riley GJ Scott CM Shaw TE Starr KR Stemp G Thewlis KM Thomas DR Thompson M Vong AK Watson JM 《Bioorganic & medicinal chemistry letters》2005,15(3):737-741
Starting from a high throughput screening hit, a series of 3,4-dihydro-2H-benzoxazinones has been identified with both high affinity for the 5-HT(1A) receptor and potent 5-HT reuptake inhibitory activity. The 5-(2-methyl)quinolinyloxy derivative combined high 5-HT(1A/1B/1D) receptor affinities with low intrinsic activity and potent inhibition of the 5-HT reuptake site (pK(i)8.2). This compound also had good oral bioavailability and brain penetration in the rat. 相似文献
19.
Hayashi R Ohmori E Isogaya M Moriwaki M Kumagai H 《Bioorganic & medicinal chemistry letters》2006,16(15):4045-4047
A series of novel indolylpiperidine derivatives were synthesized and assessed for their pharmacological profiles at alpha1 adrenoceptor subtypes by in vitro binding studies at rat alpha1A and alpha1B receptors. Compound 11 was a potent (Ki=0.63 nM) and selective (approximately 30-fold more selective for the alpha1B receptor than for the alpha1A receptor) alpha1B adrenoceptor antagonist. 相似文献
20.
Stefanachi A Brea JM Cadavid MI Centeno NB Esteve C Loza MI Martinez A Nieto R Raviña E Sanz F Segarra V Sotelo E Vidal B Carotti A 《Bioorganic & medicinal chemistry》2008,16(6):2852-2869
A large series of piperazin-, piperidin- and tetrahydroisoquinolinamides of 4-(1,3-dialkyl-9-deazaxanthin-8-yl)phenoxyacetic acid were prepared through conventional or multiple parallel syntheses and evaluated for their binding affinity at the recombinant human adenosine receptors, chiefly at the hA(2B) and hA(2A) receptor subtypes. Several ligands endowed with high binding affinity at hA(2B) receptors, excellent selectivity over hA(2A) and hA(3) and a significant, but lower, selectivity over hA(1) were identified. Among them, piperazinamide derivatives 23 and 52, and piperidinamide derivative 69 proved highly potent at hA(2B) (K(i)=11, 2 and 5.5 nM, respectively) and selective towards hA(2A) (hA(2A)/hA(2B) SI=912, 159 and 630, respectively), hA(3) (hA(3)/hA(2B) SI=>100, 3090 and >180, respectively) and hA(1) (hA(1)/hA(2B) SI=>100, 44 and 120, respectively), SI being the selectivity index. A number of selected ligands tested in functional assays in vitro showed very interesting antagonist activities and efficacies at both A(2A) and A(2B) receptor subtypes, with pA(2) values close to the corresponding pK(i)s. Structure-affinity and structure-selectivity relationships suggested that the binding potency at the hA(2B) receptor may be increased by lipophilic substituents at the N4-position of piperazinamides and that an ortho-methoxy substituent at the 8-phenyl ring and alkyl groups at N1 larger than the ones at N3, in the 9-deazaxanthine ring, may strongly enhance the hA(2A)/hA(2B) SI. 相似文献