Comparative molecular field analysis of fenoterol derivatives interacting with an agonist-stabilized form of the β2-adrenergic receptor
摘要:
The beta(2)-adrenergic receptor (beta(2)-AR) agonist [H-3]-(R,R')-methoxyfenoterol was employed as the marker ligand in displacement studies measuring the binding affinities (K-i values) of the stereoisomers of a series of 4'-methoxyfenoterol analogs in which the length of the alkyl substituent at alpha' position was varied from 0 to 3 carbon atoms. The binding affinities of the compounds were additionally determined using the inverse agonist [H-3]-CGP-12177 as the marker ligand and the ability of the compounds to stimulate cAMP accumulation, measured as EC50 values, were determined in HEK293 cells expressing the beta(2)-AR. The data indicate that the highest binding affinities and functional activities were produced by methyl and ethyl substituents at the alpha' position. The results also indicate that the K-i values obtained using [H-3]-(R,R')methoxyfenoterol as the marker ligand modeled the EC50 values obtained from cAMP stimulation better than the data obtained using [H-3]-CGP-12177 as the marker ligand. The data from this study was combined with data from previous studies and processed using the Comparative Molecular Field Analysis approach to produce a CoMFA model reflecting the binding to the beta(2)-AR conformation probed by [H-3]-(R,R')-4'-methoxyfenoterol. The CoMFA model of the agonist-stabilized beta(2)-AR suggests that the binding of the fenoterol analogs to an agonist-stabilized conformation of the beta(2)-AR is governed to a greater extend by steric effects than binding to the [H-3]-CGP-12177-stabilized conformation(s) in which electrostatic interactions play a more predominate role. (C) 2013 Elsevier Ltd. All rights reserved.
The macrocyclic antibiotic mangrolide A has been described to exhibit potent activity against a number of clinically important Gram‐negative pathogens. Reported is the first enantioselective totalsynthesis of mangrolide A and derivatives. Salient features of this synthesis include a highly convergent macrocycle preparation, stereoselective synthesis of the disaccharide moiety, and two β‐selective
Synthesis of Chiral Amino Alcohols Embodying the Bispidine Framework and Their Application as Ligands in Enantioselectively Catalyzed Additions to CO and CC Groups
course of enantioselective transformations, bispidine amino alcohols built up by these two routes were investigated as chiralligands in the enantioselectively catalyzed addition of diethylzinc to aldehydes and chalcone. In general, tridentate ligands containing one chiral amino alcohol fragment and a second amino substituent without a stereogenic center were more efficient than tetradentate ligands with
已经开发了两种普遍适用的合成包含双吡啶骨架的手性氨基醇的路线。在线性路线 A 中,双吡啶骨架是由手性伯胺通过中间体形成哌啶酮和双吡啶酮依次构建的。在收敛路线 B 中,首先形成非手性双吡啶,然后通过氮碱与手性亲电试剂的反应引入 N-取代基。为了确定双吡啶核心及其 N 取代基是否能影响对映选择性转化的空间过程,研究了通过这两种途径构建的双吡啶氨基醇作为手性配体在二乙基锌对醛和查耳酮的对映选择性催化加成中。一般来说,含有一个手性氨基醇片段和没有立体中心的第二个氨基取代基的三齿配体比具有两个氨基醇结构单元的四齿配体更有效。使用最好的配体,二乙基锌对芳香族和脂肪族醛的对映选择性加成以 83-98% ee 进行,二乙基锌向查耳酮的镍催化加成达到 85% ee。
[EN] CD73 INHIBITORS<br/>[FR] INHIBITEURS DE CD73
申请人:LILLY CO ELI
公开号:WO2019168744A1
公开(公告)日:2019-09-06
The present invention provides 5-[5]-[2-cycloa Ikyl ]-6-pyridazin-3-yl ]- IH-pyrimidine-2,4-dione compounds, or pharmaceutically acceptable salts thereof, that inhibit the activity of CD73 and are useful in treating cancer. (Formula (I))
Stereoselective Synthesis of Chiral 4-(1-Chloroalkyl)-β-Lactams Starting from Amino Acids and Their Transformation into Functionalized Chiral Azetidines and Pyrrolidines
作者:Stijn Dekeukeleire、Matthias D’hooghe、Karl W. Törnroos、Norbert De Kimpe
DOI:10.1021/jo101220q
日期:2010.9.3
α-chlorination procedures. The latter aldehydes proved to be useful starting materials for the stereoselective Staudinger synthesis of (3S,4S)-4-[(1S)-1-chloroalkyl]azetidin-2-ones in high diastereomeric ratios and good overall yields, which were used as chiral building blocks for the preparation of a number of azetidines and pyrrolidines.
Determination of the Absolute Configuration of β-Chiral Primary Alcohols Using the Competing Enantioselective Conversion Method
作者:Alexander S. Burns、Alexander J. Wagner、Jennifer L. Fulton、Kyle Young、Armen Zakarian、Scott. D. Rychnovsky
DOI:10.1021/acs.orglett.7b01189
日期:2017.6.2
A method for determining the absoluteconfiguration of β-chiral primary alcohols has been developed. Enantioenriched alcohols were acylated in the presence of either enantiomer of the enantioselective acylation catalyst HBTM, and the faster reaction was determined by measuring product conversion using 1H NMR spectroscopic analysis. An empirical mnemonic was developed that correlates the absolute configuration
已经开发出确定β-手性伯醇的绝对构型的方法。在对映选择性酰化催化剂HBTM的任何一种对映异构体的存在下,将富含对映体的醇酰化,并通过使用1 H NMR光谱分析测量产物转化率来确定更快的反应。开发了经验助记符,其将醇的绝对构型与更快反应的催化剂相关联。该方法成功的底物包括在立体异构中心带有“指导基团”的伯醇。指导基团包括芳烃,杂芳烃,烯酮和卤化物。