排序方式: 共有7条查询结果,搜索用时 171 毫秒
1
1.
2.
Synthesis of potent and orally efficacious 11β-hydroxysteroid dehydrogenase type 1 inhibitor HSD-016
Wan ZK Chenail E Li HQ Kendall C Wang Y Gingras S Xiang J Massefski WW Mansour TS Saiah E 《The Journal of organic chemistry》2011,76(17):7048-7055
Cortisol and the glucocorticoid receptor (GR) signaling pathway has been linked to the development of diabetes and metabolic syndrome. In vivo, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of inactive cortisone to its active form, cortisol. Existing clinical data have supported 11β-HSD1 as a valid therapeutic target for type 2 diabetes. In our research program, (R)-1,1,1-trifluoro-2-(3-((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsulfonyl)phenyl)propan-2-ol (HSD-016) was discovered to be a potent, selective, and efficacious 11β-HSD1 inhibitor and advanced as a clinical candidate. Herein, a reliable and scalable synthesis of HSD-016 is described. Key transformations include an asymmetric synthesis of a chiral tertiary alcohol via Sharpless dihydroxylation, epoxide formation, and subsequent mild reduction. This route ensured multikilogram quantities of HSD-016 necessary for clinical studies. 相似文献
3.
Remsing RC Hernandez G Swatloski RP Massefski WW Rogers RD Moyna G 《The journal of physical chemistry. B》2008,112(35):11071-11078
The solvation of carbohydrates in N, N'-dialkylimidazolium ionic liquids (ILs) was investigated by means of 13C and 35/37Cl NMR relaxation and 1H pulsed field gradient stimulated echo (PFG-STE) diffusion measurements. Solutions of model sugars in 1- n-butyl-3-methylimidazolium chloride ([C4mim]Cl), 1-allyl-3-methylimidazolium chloride ([CC2mim]Cl), and 1-ethyl-3-methylimidazolium acetate ([C2mim][OAc]) were studied to evaluate the effects of cation and anion structure on the solvation mechanism. In all cases, the changes in the relaxation times of carbon nuclei of the IL cations as a function of carbohydrate concentration are small and consistent with the variation in solution viscosities. Conversely, the 35/37Cl and 13C relaxation rates of chloride ions and acetate ion carbons, respectively, have a strong dependency on sugar content. For [C2mim][OAc], the correlation times estimated from 13C relaxation data for both ions reveal that, as the carbohydrate concentration increases, the reorientation rate of the anion decreases faster than that of the cation. Although not as marked as the variations observed in the relaxation data, similar trends were obtained from the analysis of cation and, in the case of [C2mim][OAc], anion self-diffusion coefficients of the sugar/IL systems. Our results show that the interactions between the IL cation and the solutes are nonspecific, confirm that the process is governed by the interactions between the IL anion and the carbohydrate, and, more importantly, indicate no change in the solvation mechanism regardless of the structure of the anion. 相似文献
4.
Dimethyl sulfoxide causes alpha,beta-dihalopropanoate derivatives to undergo efficient, selective dehydrohalogenation to form alpha-haloacrylate analogues. A variety of alpha-halo Michael acceptors were prepared in dimethyl sulfoxide under mild, base-free conditions, including the preparation of alpha-bromoacrolein and alpha-chloro- and bromoacrylonitriles. Synthesis of these molecules has been reported in the literature to be difficult. Among all the existing dehydrohalogenation procedures, this protocol is the most facile, practical, and environmentally benign process. 相似文献
5.
Massefski W 《Journal of magnetic resonance (San Diego, Calif. : 1997)》2008,192(2):323-328
Stopped-flow NMR at capillary scale has many advantages over traditional methods of introducing the sample into the probe, particularly when large numbers of samples must be examined. This work describes application of a simple method for direct visualization of a sample inside the flow cell of flow NMR systems to capillary scale analysis. We describe the details of the method and show how it can be used to measure the optimum flow rate for a capillary NMR system and how to determine the optimum sampling efficiency for small samples. 相似文献
6.
Gavrin LK Lee A Provencher BA Massefski WW Huhn SD Ciszewski GM Cole DC McKew JC 《The Journal of organic chemistry》2007,72(3):1043-1046
This work describes two distinct routes to prepare pyrazolo[1,5-alpha]pyrimidin-7-ones and two distinct routes to prepare pyrazolo[1,5-alpha]pyrimidin-5-ones. Use of 1,3-dimethyluracil as the electrophile in the preparation of the pyrimidin-5-one regioisomer represents a correction of previously reported results. Also, a novel reaction to prepare this isomer was identified and the reaction mechanism elucidated. This work provides the experimentalist with complimentary synthetic pathways that afford either the pyrimidin-7-one or the pyrimidin-5-one regioisomer. 相似文献
7.
Anthony J. Rojas Justin M. Wolfe Heemal H. Dhanjee Ivan Buslov Nicholas L. Truex Richard Y. Liu Walter Massefski Bradley L. Pentelute Stephen L. Buchwald 《Chemical science》2022,13(40):11891
The synthesis of palladium oxidative addition complexes derived from unprotected peptides is described. Incorporation of 4-halophenylalanine into a peptide during solid phase peptide synthesis allows for subsequent oxidative addition at this position upon treatment with a palladium precursor and suitable ligand. The resulting palladium–peptide complexes are solid, storable, water-soluble, and easily purified via high-performance liquid chromatography. These complexes react with thiols in aqueous buffer, offering an efficient method for bioconjugation. Using this strategy, peptides can be functionalized with small molecules to prepare modified aryl thioether side-chains at low micromolar concentrations. Additionally, peptide–peptide and peptide–protein ligations are demonstrated under dilute aqueous conditions.Peptides bearing palladium oxidative addition complexes can be synthesized from the parent aryl halide containing substrates and react with thiol functional groups of small molecules, peptides, and proteins at low micromolar concentrations. 相似文献
1