- Discovery of (E)-4-styrylphenoxy-propanamide: A dual PPARα/γ partial agonist that regulates high-density lipoprotein-cholesterol levels, modulates adipogenesis, and improves glucose tolerance in diet-induced obese mice
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Peroxisome proliferator-activated receptors are promising therapeutic targets for metabolic diseases, including obesity, diabetes, and dyslipidemia. This study describes the design, synthesis and pharmacological evaluation of stilbene-based compounds as d
- Dutra, Luiz A.,Lacerda, Mariella G.,Destro Inácio, Maiara,Martins, Johnny W.L.,Lopes Silva, Ana C.,Bento da Silva, Patricia,Chorilli, Marlus,Amato, Angélica A.,Baviera, Amanda M.,Passarelli, Marisa,Guido, Rafael V.C.,Dos Santos, Jean L.
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supporting information
(2022/01/26)
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- Development of Alectinib-Based PROTACs as Novel Potent Degraders of Anaplastic Lymphoma Kinase (ALK)
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A series of novel anaplastic lymphoma kinase (ALK) degraders were designed and synthesized based on proteolysis-targeting chimera (PROTAC) technology by linking two alectinib analogs (36 and 37) with pomalidomide through linkers of different lengths and types. The most promising degrader 17 possessed a high ALK-binding affinity and potent antiproliferative activity in the ALK-dependent cell lines and did not exhibit obvious cytotoxicity in ALK fusion-negative cells. More importantly, the efficacy of compound 17 in a Karpas 299 xenograft mouse model was further evaluated based on its ALK-sustained degradation ability in vivo. The reduction in tumor weight in the compound 17-treated group (10 mg/kg/day, I.V.) reached 75.82%, while alectinib reduced tumor weight by 63.82% at a dose of 20 mg/kg/day (P.O.). Taken together, our findings suggest that alectinib-based PROTACs associated with the degradation of ALK may have promising beneficial effects for treating ALK-driven malignancies.
- Xie, Shaowen,Sun, Yuan,Liu, Yulin,Li, Xinnan,Li, Xinuo,Zhong, Wenyi,Zhan, Feiyan,Zhu, Jingjie,Yao, Hong,Yang, Dong-Hua,Chen, Zhe-Sheng,Xu, Jinyi,Xu, Shengtao
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p. 9120 - 9140
(2021/07/20)
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- Method for synthesizing netarsudil intermediate
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The invention relates to a method for synthesizing a netarsudil intermediate that is 6-aminoisoquinoline. The method includes (1) dissolving 2-bromo-2-methylpropionic acid; (2) adding oxalyl chloride,and then reacting the mixture; (3) after the reaction is completed, pouring the reaction solution into aqueous ammonia, stirring the mixture, performing filtration and drying a product. The method utilizes conventional and easily available chemical materials, and has characteristics of mild reactions, a short route and a high yield.
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Paragraph 0067-0073; 0088-0093; 0109-0115
(2019/11/20)
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- Method and using tracer charged ion channel
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The invention provides compounds, compositions, methods, and kits for the treatment of pain, itch, and neurogenic inflammation.
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Paragraph 0245; 0247; 0248-0250
(2018/08/20)
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- Synthesis method for alectinib hydrochloride intermediate
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The invention discloses a synthesis method for an alectinib hydrochloride intermediate. The synthesis method includes the following steps: 1) with 2-bromo-2-methylpropionic acid as an initial raw material, adding thionyl chloride to perform a chlorination reaction to obtain a compound (I); 2) adding ethylbenzene to the compound (I) and adding anhydrous aluminum trichloride as a catalyst to perform a substitution reaction to obtain a compound (II); 3) dissolving the compound (II) in an organic solvent, adding HC(OMe)3 and a catalyst ZnCl2, performing heat reflux until a rearrangement reaction is completely finished to obtain a compound (III); 4) dissolving the compound (III) in an organic solvent, adding iodine and iodic acid to perform a catalytic reaction to generate a compound (IV); and 5) under alkaline condition, hydrolyzing the compound (IV) to produce the target product, alectinib hydrochloride intermediate. The synthesis method is simple in operations, has high yield and is lower in cost.
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Paragraph 0036; 0044; 0050; 0051
(2017/10/12)
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- BETA-LACTAMASE INHIBITORS
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Described herein are compounds and compositions that modulate the activity of beta -lactamases. In some embodiments, the compounds described herein inhibit beta-lactamase. In certain embodiments, the compounds described herein are useful in the treatment of bacterial infections.
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Paragraph 0385
(2017/04/08)
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- Synthesis, enantioresolution, and activity profile of chiral 6-methyl-2,4-disubstituted pyridazin-3(2H)-ones as potent N-formyl peptide receptor agonists
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A series of chiral pyridazin-3(2H)-ones was synthesized, separated as pure enantiomers, and evaluated for N-formyl peptide receptor (FPR) agonist activity. Characterization of the purified enantiomers using combined chiral HPLC and chiroptical studies (circular dichroism, allowed unambiguous assignment of the absolute configuration for each pair of enantiomers). Evaluation of the ability of racemic mixtures and purified enantiomers to stimulate intracellular Ca 2+ flux in FPR-transfected HL-60 cells and human neutrophils and to induce β-arrestin recruitment in FPR-transfected CHO-K1 cells showed that many enantiomers were potent agonists, inducing responses in the sub-micromolar to nanomolar range. Furthermore, FPRs exhibited enantiomer selectivity, generally preferring the R-(-)-forms over the S-(+)-enantiomers. Finally, we found that elongation of the carbon chain in the chiral center of the active compounds generally increased biological activity. Thus, these studies provide important new information regarding molecular features involved in FPR ligand preference and report the identification of a novel series of FPR agonists.
- Cilibrizzi, Agostino,Schepetkin, Igor A.,Bartolucci, Gianluca,Crocetti, Letizia,Dal Piaz, Vittorio,Giovannoni, Maria Paola,Graziano, Alessia,Kirpotina, Liliya N.,Quinn, Mark T.,Vergelli, Claudia
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experimental part
p. 3781 - 3792
(2012/08/28)
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- COMPOUNDS WHICH SELECTIVELY MODULATE THE CB2 RECEPTOR
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Compounds of formula (I) are disclosed. Compounds according to the invention bind to and are agonists, antagonists or inverse agonists of the CB2 receptor, and are useful for treating inflammation. Those compounds which are agonists are additionally useful for treating pain.
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Page/Page column 41-42
(2010/12/31)
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- 1, 2 DISUBSTITUTED HETEROCYCLIC COMPOUNDS
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1,2-disubstituted heterocyclic compounds which are inhibitors of phosphodiesterase 10 are described. Also described are processes, pharmaceutical compositions, pharmaceutical preparations and pharmaceutical use of the compounds in the treatment of mammals, including human(s) for central nervous system (CNS) disorders and other disorders which may affect CNS function. Among the disorders which may be treated are neurological, neurodegenerative and psychiatric disorders including, but not limited to, those associated with cognitive deficits or schizophrenic symptoms.
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Page/Page column 80
(2010/01/30)
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- AMINE AND ETHER COMPOUNDS WHICH MODULATE THE CB2 RECEPTOR
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Compounds which modulate the CB2 receptor are disclosed. The compounds are useful for treating CB2 receptor-mediated diseases such as pain.
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Page/Page column 38
(2009/10/18)
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- Compounds Which Modulate The CB2 Receptor
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Compound of formula (I) are disclosed. Compounds according to the invention bind to and are agonists, antagonists or inverse agonists of the CB2 receptor, and are useful for treating inflammation. Those compounds which are agonists are additionally useful
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Page/Page column 20
(2008/06/13)
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- Compounds which Modulate the CB2 Receptor
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Compounds of formula (I) are disclosed. Compounds according to the invention bind to and are agonists, antagonists or inverse agonists of the CB2 receptor, and are useful for treating inflammation. Those compounds which are agonists are additionally usefu
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Page/Page column 12
(2008/06/13)
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- Monohydroxy terminally functionalised poly(methyl methacrylate) from atom transfer radical polymerisation
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Atom transfer radical polymerisation (ATRP) of methyl methacrylate with a pyridinecarbaldehyde imine copper(I) catalyst and hydroxy functional alkyl bromide initiator leads to α-hydroxy functional PMMA with controlled Mn and PDI 1.20 without the use of protecting group chemistry.
- Haddleton, David M.,Waterson, Carl,Derrick, Peter J.,Jasieczek, Christina B.,Shooter, Andrew J.
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p. 683 - 684
(2007/10/03)
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