79-44-7Relevant academic research and scientific papers
Discovery of 4-((2 S,4 S)-4-Ethoxy-1-((5-methoxy-7-methyl-1 H-indol-4-yl)methyl)piperidin-2-yl)benzoic Acid (LNP023), a Factor B Inhibitor Specifically Designed to Be Applicable to Treating a Diverse Array of Complement Mediated Diseases
Mainolfi, Nello,Ehara, Takeru,Karki, Rajeshri G.,Anderson, Karen,Mac Sweeney, Aengus,Liao, Sha-Mei,Argikar, Upendra A.,Jendza, Keith,Zhang, Chun,Powers, James,Klosowski, Daniel W.,Crowley, Maura,Kawanami, Toshio,Ding, Jian,April, Myriam,Forster, Cornelia,Serrano-Wu, Michael,Capparelli, Michael,Ramqaj, Rrezarta,Solovay, Catherine,Cumin, Frederic,Smith, Thomas M.,Ferrara, Luciana,Lee, Wendy,Long, Debby,Prentiss, Melissa,De Erkenez, Andrea,Yang, Louis,Liu, Fang,Sellner, Holger,Sirockin, Finton,Valeur, Eric,Erbel, Paulus,Ostermeier, Daniela,Ramage, Paul,Gerhartz, Bernd,Schubart, Anna,Flohr, Stefanie,Gradoux, Nathalie,Feifel, Roland,Vogg, Barbara,Wiesmann, Christian,Maibaum, Jürgen,Eder, J?rg,Sedrani, Richard,Harrison, Richard A.,Mogi, Muneto,Jaffee, Bruce D.,Adams, Christopher M.
, p. 5697 - 5722 (2020)
The alternative pathway (AP) of the complement system is a key contributor to the pathogenesis of several human diseases including age-related macular degeneration, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and various glomerular diseases. The serine protease factor B (FB) is a key node in the AP and is integral to the formation of C3 and C5 convertase. Despite the prominent role of FB in the AP, selective orally bioavailable inhibitors, beyond our own efforts, have not been reported previously. Herein we describe in more detail our efforts to identify FB inhibitors by high-throughput screening (HTS) and leveraging insights from several X-ray cocrystal structures during optimization efforts. This work culminated in the discovery of LNP023 (41), which is currently being evaluated clinically in several diverse AP mediated indications.
Preparation method of dimethyl carbamoyl chloride
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Paragraph 0036-0044, (2021/05/12)
The invention relates to a preparation method of dimethyl carbamoyl chloride, which is characterized in that dimethyl carbamoyl chloride is directly synthesized by dimethylamine chloride and carbon monoxide under the action of a catalyst, the catalyst is optimized, and a special reactor is designed, so that efficient and green production of the dimethyl carbamoyl chloride is realized. The invention provides an efficient and green intermediate synthesis method for synthesis of pesticides pirimicarb and triazamate and a large number of pesticides.
Dual inhibitors of Interleukin-6 and acetylcholinesterase for treatment of Alzheimer's disease: Design, docking, synthesis and biological evaluation
Bansal, Yogita,Kaur, Sukhvir
, (2021/11/13)
Multitarget compounds intercept two or more functionally complementary pathways simultaneously, and are therefore considered to have potential in effectively treating complex multifactorial diseases like Alzheimer's disease (AD). In the present study, novel molecules are designed by coupling a chromone and a N,N-disubstituted carbamoyl amine as pharmacophore for interleukin-6 (IL-6) and acetylcholinesterase (AChE) inhibition, respectively. Four series (Y1–Y4) of 40 compounds are designed by using alkyl linkers of different lengths (1–4 carbon atoms) for the coupling of the two selected pharmacophore. Docking of all designed compounds in AChE leads to the identification of twelve best fit compounds (Docking score >8.3). The data suggests that a 1- or 2-carbon atom linker is the most conducive to orient the pharmacophore for optimum binding with AChE active site. The predicted ADME properties of the 12 selected compounds suggest that these can cross the blood brain barrier (BBB) with good oral bioavailability. These compounds are synthesised and evaluated for anti-AChE activity. Five compounds, showing >45% inhibition of AChE, are further evaluated for IL-6 inhibitory activity. Compound Y1f is found to be the most potent inhibitor of both AChE and IL-6 (IC50 0.7 and 0.8 ?μM, respectively). It suggests that a chromone moiety connected to a piperidine ring through a 1-carbon atom linker may provide a useful template to medical chemists for the development of new chemical entities effective against AD.
Cannabidiol carbamate compound, pharmaceutical preparation, preparation method and application
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Paragraph 0087-0091, (2021/01/30)
The invention relates to a cannabidiol carbamate compound, a medicinal preparation, a preparation method and application, and belongs to the field of compounds for treating and preventing diseases related to aging, Alzheimer's disease and Parkinson's disease. The compound has a structure shown as a formula I or a pharmaceutically acceptable salt of the structure shown as the formula I. The compound has good butyrylcholine esterase resisting activity, shows good application prospect in treatment of Alzheimer's disease, and shows good application potential.
Synthesis and Biological Evaluation of Celastrol Derivatives with Improved Cytotoxic Selectivity and Antitumor Activities
Feng, Jia-Hao,He, Qi-Wei,Hou, Ji-Qin,Hu, Xiao-Long,Long, Huan,Wang, Bao-Lin,Wang, Hao,Wang, Quan,Wang, Rong,Ye, Wen-Cai,Zhang, Li-Xin,Zhang, Xiao-Qi
, p. 1954 - 1966 (2021/07/20)
Cdc37 associates kinase clients to Hsp90 and promotes the development of cancers. Celastrol, a natural friedelane triterpenoid, can disrupt the Hsp90-Cdc37 interaction to provide antitumor effects. In this study, 31 new celastrol derivatives, 2a - 2d , 3a - 3g , and 4a - 4t , were designed and synthesized, and their Hsp90-Cdc37 disruption activities and antiproliferative activities against cancer cells were evaluated. Among these compounds, 4f , with the highest tumor cell selectivity (15.4-fold), potent Hsp90-Cdc37 disruption activity (IC50= 1.9 μM), and antiproliferative activity against MDA-MB-231 cells (IC50= 0.2 μM), was selected as the lead compound. Further studies demonstrated 4f has strong antitumor activities both in vitro and in vivo through disrupting the Hsp90-Cdc37 interaction and inhibiting angiogenesis. In addition, 4f exhibited less toxicity than celastrol and showed a good pharmacokinetics profile in vivo. These findings suggest that 4f may be a promising candidate for development of new cancer therapies.
Novel cannabidiol?carbamate hybrids as selective BuChE inhibitors: Docking-based fragment reassembly for the development of potential therapeutic agents against Alzheimer's disease
Jiang, Xia,Liu, Xin-Hua,Shi, Jingbo,Tang, Wenjian,Wang, Sheng,Wu, Chengyao,Xu, Yingying,Zha, Liang,Zhang, Jing,Zhang, Ziwen,Zuo, Jiawei
, (2021/08/10)
Cannabidiol (CBD) and rivastigmine have been launched as drugs for treating dementia and cholinesterases (ChEs) are ideal drug targets. This study focused on developing novel ChE inhibitors as drug leads against dementia through molecular modeling and fragment reassembly approaches. A potent carbamate fragment binding to active site gorge of BuChE was found via a docking-based structural splicing approach, thus, 17 novel compounds were designed by structural reassembly. Compound C16 was identified as a highly selective potent BuChE inhibitor (IC50 = 5.3 nM, SI > 4000), superior to CBD (IC50 = 0.67 μM). C16 possessed BBB penetrating ability, benign safety, neuroprotection, antioxidant and pseudo-irreversible BuChE inhibition (Kd = 13 nM, k2 = 0.26 min?1), showing good drug-like properties. In vivo studies confirmed that C16 significantly ameliorated the scopolamine-induced cognition impairment, almost entirely recovered the Aβ1?42 (icv)-impaired cognitive function to the normal level, showed better behavioral performance than donepezil and good anti-amyloidogenic effect. Hence, the potential BuChE inhibitor C16 can be developed as a promising disease-modifying treatment of AD.
Preparation method of dimethylcarbamoyl chloride
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Paragraph 0023-0034, (2019/03/08)
The invention discloses a preparation method of dimethylcarbamoyl chloride. The preparation method comprises the following steps: simultaneously introducing dimethylamine and phosgene into a micro-reactor to perform the reaction to obtain the dimethylcarbamoyl chloride. The dimethylcarbamoyl chloride prepared in the preparation method disclosed by the invention is high in content, the content reaches 98.5 to 99 percent, and the yield is greatly increased and can reach 95.0 to 96.2 percent (referring to dimethylamine). The preparation method disclosed by the invention has the advantages of simple operation, high yield, less waste, safety, environmental protection and the like, is suitable for industrialized production and good in application value and application prospect.
Design, synthesis and biological evaluation of dual acetylcholinesterase and phosphodiesterase 5A inhibitors in treatment for Alzheimer's disease
Zhou, Li-yun,Zhu, Yao,Jiang, Yu-ren,Zhao, Xiong-jie,Guo, Dong
supporting information, p. 4180 - 4184 (2017/08/23)
With the recent research advances in molecular biology and technology, multiple credible hypotheses about the progress of Alzheimer's disease (AD) have been proposed; multi-target drugs have emerged as an innovative therapeutic approach for AD. Current clinical therapy for AD patients is mainly palliative treatment targeting acetylcholinesterase (AChE). Inhibition of phosphodiesterase 5A (PDE5A) has recently been validated as a potentially novel therapeutic approach for Alzheimer's disease (AD). In this work, series of new compounds were designed, synthesized and evaluated as dual cholinesterase and PDE5A inhibitor. Biological results revealed that some of these compounds display good biological activities against AChE with IC50 values about 44.67–169.80 nM (donepezil IC50 50.12 nM). Notably, compound 12 presented potent activities against PDE5A with IC50 values about 50 μM (sildenafil IC50 12.59 μM), and some of these compounds showed low cell toxicity to A549 cells in vitro.
Design, synthesis and biological evaluation of 4'-aminochalcone-rivastigmine hybrids as multifunctional agents for the treatment of Alzheimer's disease
Xiao, Ganyuan,Li, Yan,Qiang, Xiaoming,Xu, Rui,Zheng, Yunxiaozhu,Cao, Zhongcheng,Luo, Li,Yang, Xia,Sang, Zhipei,Su, Fu,Deng, Yong
, p. 1030 - 1041 (2017/02/05)
A series of 4'-aminochalcone-revastigmine hybrids were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease. The results showed that most of these compounds exhibited good multifunctional activities. In particular, compound 6c displayed the best inhibitory potency on acetylcholinesterase (IC50= 4.91 μM), and significant antioxidative activity with a value 2.83-fold of Trolox. The kinetic analysis of AChE inhibition revealed that 6c showed mixed-type inhibition, binding simultaneously to the catalytic active site and peripheral anionic site of AChE. In addition, 6c inhibited self-induced Aβ1-42aggregation and Cu2+-induced Aβ1-42aggregation by 89.5% and 79.7% at 25 μM respectively, as well as acted as a selective monoamine oxidase B inhibitor (IC50= 0.29 μM) and a selective biometal chelator. Furthermore, 6c could cross the blood-brain barrier in vitro. Based on these results, Compound 6c could be considered as a very promising lead compound for Alzheimer's disease.
One-Pot Synthesis of O -Aryl Carbamates
Varjosaari, Sami E.,Suating, Paolo,Adler, Marc J.
, p. 43 - 47 (2015/12/26)
A simple, versatile, one-pot procedure for the synthesis of substituted O-aryl carbamates has been developed, and a protocol is henceforth described. N-Substituted carbamoyl chloride is formed in situ and subsequently reacted with a substituted phenol, avoiding the direct manipulation of sensitive reactants. This procedure offers an economical and efficient route to many compounds of interest.
