共查询到20条相似文献,搜索用时 31 毫秒
1.
Hu B Malamas M Ellingboe J Largis E Han S Mulvey R Tillett J 《Bioorganic & medicinal chemistry letters》2001,11(8):981-984
As part of our investigation into the development of potent and selective human beta3 agonists, a series of thiazolidinedione analogues was prepared and evaluated for their biological activity on the human beta3-adrenergic receptor. The oxadiazolidinedione derivative 17 was found to be the most potent and selective compound in this study, with an EC50 value of 0.02 microM at the beta3 receptor, 259-fold selectivity over the beta1 receptor, and 745-fold selectivity over the beta2 receptor. 相似文献
2.
Parmee ER Brockunier LL He J Singh SB Candelore MR Cascieri MA Deng L Liu Y Tota L Wyvratt MJ Fisher MH Weber AE 《Bioorganic & medicinal chemistry letters》2000,10(20):2283-2286
Tetrahydroisoquinoline derivatives containing a 4-(hexylureido)benzenesulfonamide were examined as human beta3 adrenergic receptor (AR) agonists. Notably, 4,4-biphenyl derivative 9 was a 6 nM full agonist of the beta3 AR. Naphthyloxy compound 18 (beta3 EC50 = 78 nM) did not activate the beta1 and beta2 ARs at 10 microM, and showed >1000-fold selectivity over binding to the beta1 and beta2 ARs. 相似文献
3.
Brockunier LL Parmee ER Ok HO Candelore MR Cascieri MA Colwell LF Deng L Feeney WP Forrest MJ Hom GJ MacIntyre DE Tota L Wyvratt MJ Fisher MH Weber AE 《Bioorganic & medicinal chemistry letters》2000,10(18):2111-2114
Compounds containing a 1,2,3-triazole-substituted benzenesulfonamide were prepared and found to be potent and selective human beta3-adrenergic receptor agonists. The most interesting compound, trifluoromethylbenzyl analogue 12e (beta3 EC50 = 3.1 nM with >1500-fold selectivity over binding to both beta1- and beta2 receptors), stimulates lipolysis in the rhesus monkey (ED50 = 0.36 mg/kg) and is 25% orally bioavailable in the dog. 相似文献
4.
Ji M Chen J Ding K Wu X Varady J Levant B Wang S 《Bioorganic & medicinal chemistry letters》2005,15(6):1701-1705
A hexahydropyrazinoquinoline (compound 5c) was previously discovered as a novel D3 ligand with a moderate binding affinity to the D3 receptor (Ki=304 nM) but no selectivity over the D1-like and D2-like receptors. In this study, we wish to report the design, synthesis and structure-activity relationship studies of a series of novel hexahydropyrazinoquinolines. Our efforts resulted in new compounds with improved binding affinity and selectivity. Among them, compound 12d has a Ki value of 2.6 nM for its binding affinity to the D3 receptor and has >2000- and 99-fold selectivity over the D1-like and D2-like receptors, respectively, representing a potent and selective D3 ligand. 相似文献
5.
Lum C Kahl J Kessler L Kucharski J Lundström J Miller S Nakanishi H Pei Y Pryor K Roberts E Sebo L Sullivan R Urban J Wang Z 《Bioorganic & medicinal chemistry letters》2008,18(12):3578-3581
The discovery of two classes of pyrimidine-based inhibitors of GSK-3 is described. Optimization of these series led to inhibitors with IC(50)<10nM and >100-fold selectivity over Aurora A kinase. A proposed binding mode of 21b is presented. One compound (33) of the pyrimidine series showed promising pharmacokinetic parameters. 相似文献
6.
Ok HO Reigle LB Candelore MR Cascieri MA Colwell LF Deng L Feeney WP Forrest MJ Hom GJ MacIntyre DE Strader CD Tota L Wang P Wyvratt MJ Fisher MH Weber AE 《Bioorganic & medicinal chemistry letters》2000,10(14):1531-1534
As a part of our investigation into the development of orally bioavailable beta3 adrenergic receptor agonists, we have identified a series of substituted oxazole derivatives that are potent beta3 agonists with excellent selectivity against other beta receptors. Several of these compounds showed excellent oral bioavailability in dogs. One example, cyclopentylethyloxazole 5f is a potent beta3 agonist (EC50 = 14 nM, 84% activation) with 340-fold and 160-fold selectivity over beta1 and beta2 receptors, respectively, and has 38% oral bioavailability in dogs. 相似文献
7.
Richardson CM Williamson DS Parratt MJ Borgognoni J Cansfield AD Dokurno P Francis GL Howes R Moore JD Murray JB Robertson A Surgenor AE Torrance CJ 《Bioorganic & medicinal chemistry letters》2006,16(5):1353-1357
Crystallographic and modelling data, in conjunction with a medicinal chemistry template-hopping approach, led to the identification of a series of novel and potent inhibitors of human cyclin-dependent kinase 2 (CDK2), with selectivity over glycogen synthase kinase-3beta (GSK-3beta). One example had a CDK2 IC(50) of 120 nM and showed selectivity over GSK-3beta of 167-fold. 相似文献
8.
Roach SL Higuchi RI Adams ME Liu Y Karanewsky DS Marschke KB Mais DE Miner JN Zhi L 《Bioorganic & medicinal chemistry letters》2008,18(12):3504-3508
A series of nonsteroidal glucocorticoid receptor (GR) ligands based on a 6-indole-1,2,3,4-tetrahydroquinoline scaffold are reported. Structure-activity relationship (SAR) of the pendent indole group identified compound 20 exhibiting good GR binding affinity (K(i)=1.5nM) and 100- to 1000-fold selectivity over MR, PR, and AR while showing activity in an E-selectin repression assay. 相似文献
9.
Novel class of bivalent glutathione S-transferase inhibitors 总被引:1,自引:0,他引:1
Exploiting the principle of bivalent binding, we have designed symmetrical, bifunctional inhibitors to simultaneously occupy both active sites of cytosolic glutathione S-transferase, with enhanced specificity for the P1-1 isoform. We have prepared two series of compounds that differ in their binding domains-the first is a series of bis-glutathione conjugates, and the second is a series of compounds each possessing two equivalents of Uniblue A, an analogue of Cibacron Blue. For each series, a monofunctional reference compound was also prepared to determine the relative advantage of the bivalent inhibitors. Within each series, the most potent inhibitors exhibited IC(50) values 2 orders of magnitude lower than the relevant reference compounds. Moreover, within the bis-glutathionyl series, a 10-fold increase in selectivity was achieved for GST P1-1 over the A1-1 isoform. Isothermal titration calorimetry with a representative bis-glutathione conjugate and a monofunctional reference compound indicates that the bivalent inhibitor exhibits the expected increase in intrinsic affinity and decrease in stoichiometry relative to the monofunctional compound, supporting the overall design strategy. 相似文献
10.
Thurkauf A Chen X Zhang S Gao Y Kieltyka A Wasley JW Brodbeck R Greenlee W Ganguly A Zhao H 《Bioorganic & medicinal chemistry letters》2003,13(17):2921-2924
A series of novel 1H-pyrazolo-[3,4-c]cyclophepta[1,2-c]thiophenes was prepared and screened at selected dopamine receptor subtypes. Compound 4 (NGB 4420) displayed high affinity and selectivity (>100-fold) for the D(4) over D(2) and other CNS receptors. This compound was identified as a D(4) antagonist via its attenuation of dopamine agonist-induced GTPgamma(35)S binding at D(4) receptor. 相似文献
11.
A series of imidazole flavonoids as new type of protein tyrosine phosphatase inhibitors were synthesized and characterized. Most of them gave potent protein phosphatase 1B (PTP1B) inhibitory activities. Especially, compound 11a could effectively inhibit PTP1B with an IC50 value of 0.63 μM accompanied with high selectivity ratio (9.5-fold) over T-cell protein tyrosine phosphatase (TCPTP). This compound is cell permeable with relatively low cytotoxicity. The high binding affinity and selectivity was disclosed by molecular modeling and dynamics studies. The structural features essential for activity were confirmed by quantum chemical studies. 相似文献
12.
Ishihara T Seki N Hirayama F Orita M Koshio H Taniuchi Y Sakai-Moritani Y Iwatsuki Y Kaku S Kawasaki T Matsumoto Y Tsukamoto S 《Bioorganic & medicinal chemistry》2007,15(12):4175-4192
We describe here our investigation of a new series of orally active fXa inhibitors based on a prodrug strategy. Solid-phase parallel synthesis identified a unique series of fXa inhibitors with a substituted benzenesulfonyl group as a novel S4 binding element. This series resulted in compound 39, which exhibited potent inhibitory activity against fXa (IC50 = 13 nM) and excellent selectivity over thrombin (>7000-fold). The masking of its highly hydrophilic groups led to the creation of related prodrug 28, which demonstrated an anticoagulant effect after oral dosing. 相似文献
13.
Bratton LD Filzen GF Geyer A Hoffman JK Lu G Pulaski J Trivedi BK Unangst PC Xu X 《Bioorganic & medicinal chemistry letters》2007,17(13):3624-3629
A series of 1,4-benzyloxybenzylsulfanylaryl carboxylic acids were prepared and their activities for PPAR receptor subtypes (alpha, delta, and gamma) with potential indications for the treatment of dyslipidemia were investigated. Analog 13a displayed the greatest binding affinity (IC(50)=10nM) and selectivity (120-fold) for PPARdelta over PPARalpha. Many of the analogs investigated were found to be highly selective for PPARdelta and were dependent on the point of attachment of the substituent. In the 1,4-series, analog 28e was found to be the most potent (IC(50)=1.7 nM) and selective (>1000-fold) compound for PPARdelta. None of the compounds tested showed appreciable binding affinity for PPARgamma. 相似文献
14.
Mach RH Huang Y Freeman RA Wu L Blair S Luedtke RR 《Bioorganic & medicinal chemistry》2003,11(2):225-233
A series of 2-(5-bromo-2,3-dimethoxyphenyl)-5-(aminomethyl)-1H-pyrrole analogues was prepared and their affinity for dopamine D(2), D(3), and D(4) receptors was measured using in vitro binding assays. The results of receptor binding studies indicated that the incorporation of a pyrrole moiety between the phenyl ring and the basic nitrogen resulted in a significant increase in the selectivity for dopamine D(3) receptors. The most selective compound in this series is 2-(5-bromo-2,3-dimethoxyphenyl)-5-(2-(3-pyridal)piperidinyl)methyl-1H-pyrrole (6p), which has a D(3) receptor affinity of 4.3 nM, a 20-fold selectivity for D(3) versus D(2) receptors, and a 300-fold selectivity for D(3) versus D(4) receptors. This compound is predicted to be a useful ligand for studying the functional role of dopamine D(3) receptors in vivo. 相似文献
15.
Baell JB Duggan PJ Forsyth SA Lewis RJ Lok YP Schroeder CI 《Bioorganic & medicinal chemistry》2004,12(15):4025-4037
A benzothiazole-derived compound (4a) designed to mimic the C(alpha)-C(beta) bond vectors and terminal functionalities of Lys2, Tyr13 and Arg17 in omega-conotoxin GVIA was synthesised, together with analogues (4b-d), which had each side-chain mimic systematically truncated or eliminated. The affinity of these compounds for rat brain N-type and P/Q-type voltage gated calcium channels (VGCCs) was determined. In terms of N-type channel affinity and selectivity, two of these compounds (4a and 4d) were found to be highly promising, first generation mimetics of omega-conotoxin. The fully functionalised mimetic (4a) showed low microM binding affinity to N-type VGCCs (IC(50)=1.9 microM) and greater than 20-fold selectivity for this channel sub-type over P/Q-type VGCCs, whereas the mimetic in which the guanidine-type side chain was truncated back to an amine (4d, IC(50)= 4.1 microM) showed a greater than 25-fold selectivity for the N-type channel. 相似文献
16.
Mizuno K Sawa M Harada H Tateishi H Oue M Tsujiuchi H Furutani Y Kato S 《Bioorganic & medicinal chemistry letters》2004,14(24):5959-5962
A series of tryptamine-based 2-thiophenesulfonamide derivatives were prepared and their agonistic activity for the beta-adrenergic receptors (ARs) was evaluated. Compound 54, containing 7-methanesulfonyloxy tryptamine, was found to be a highly potent beta3-AR agonist (EC50=0.21 nM, IA=97%) with excellent selectivity for the beta3-AR over the beta1- and beta2-ARs (210- and 86-fold, respectively). 相似文献
17.
Sasikumar TK Burnett DA Zhang H Smith-Torhan A Fawzi A Lachowicz JE 《Bioorganic & medicinal chemistry letters》2006,16(17):4543-4547
Acylated and aroylated hydrazinoclozapines are highly potent dopamine D(1) antagonists that show remarkable selectivity over other dopamine receptors. The most potent compound in this series is the 2,6-dimethoxybenzhydrazide 33 with a D(1)K(i) of 1.6 nM and 212-fold selectivity over D(2) receptor. 相似文献
18.
Dow RL Schneider SR Paight ES Hank RF Chiang P Cornelius P Lee E Newsome WP Swick AG Spitzer J Hargrove DM Patterson TA Pandit J Chrunyk BA LeMotte PK Danley DE Rosner MH Ammirati MJ Simons SP Schulte GK Tate BF DaSilva-Jardine P 《Bioorganic & medicinal chemistry letters》2003,13(3):379-382
In this communication, we wish to describe the discovery of a novel series of 6-azauracil-based thyromimetics that possess up to 100-fold selectivities for binding and functional activation of the beta(1)-isoform of the thyroid receptor family. Structure-activity relationship studies on the 3,5- and 3'-positions provided compounds with enhanced TR beta affinity and selectivity. Key binding interactions between the 6-azauracil moiety and the receptor have been determined through of X-ray crystallographic analysis. 相似文献
19.
Li L Beaulieu C Carriere MC Denis D Greig G Guay D O'Neill G Zamboni R Wang Z 《Bioorganic & medicinal chemistry letters》2010,20(24):7462-7465
We discovered that the introduction of a methyl group to the benzylic position of the N-benzyl group in lead compound 1a has a dramatic effect on improving the binding selectivity of this ligand for the prostanoid receptors DP1 (receptor for prostaglandin D(2)) as compared to TP (receptor for thromboxane A(2)). Based on this discovery, we have synthesized a series of potent and highly selective DP1 antagonists. Among them, compound 1h was identified as a highly selective DP1 antagonist with excellent overall properties. It has a K(i) of 0.43 nM to DP1 in binding assay and an IC(50) of 2.5 nM in the DP1 functional assay. Its selectivity for DP1 over TP (the most potent receptor after DP1) exceeds 750-fold based on both binding and functional assays. These properties make 1h a very potent and highly selective DP1 receptor antagonist suitable for investigating the biological functions of DP1 in normal physiology and models of disease. 相似文献
20.
Woods KW Fischer JP Claiborne A Li T Thomas SA Zhu GD Diebold RB Liu X Shi Y Klinghofer V Han EK Guan R Magnone SR Johnson EF Bouska JJ Olson AM de Jong R Oltersdorf T Luo Y Rosenberg SH Giranda VL Li Q 《Bioorganic & medicinal chemistry》2006,14(20):6832-6846
A series of heteroaryl-pyridine containing inhibitors of Akt are reported. The synthesis and structure-activity relationships are discussed, leading to the discovery of a indazole-pyridine analogue (K(i)=0.16 nM). These compounds bind in the ATP binding site, are potent, ATP competitive, and reversible inhibitors of Akt activity. No selectivity amongst the Akt isoforms is observed for this analogue, but there is good selectivity against an panel of other kinases. It is least selective for other members of the AGC family of kinases but is nonetheless 40-fold selective for Akt over PKA. The compound shows cellular activity and significantly slows tumor growth in vivo. 相似文献