815-58-7Relevant academic research and scientific papers
Discovery of a Highly Selective and Potent TRPC3 Inhibitor with High Metabolic Stability and Low Toxicity
Zhang, Sicheng,Romero, Luis O.,Deng, Shanshan,Wang, Jiaxing,Li, Yong,Yang, Lei,Hamilton, David J.,Miller, Duane D.,Liao, Francesca-Fang,Cordero-Morales, Julio F.,Wu, Zhongzhi,Li, Wei
supporting information, p. 572 - 578 (2021/04/07)
The overactivation of transient receptor potential canonical 3 (TRPC3) is associated with neurodegenerative diseases and hypertension. Pyrazole 3 (Pyr3) is reported as the most selective TRPC3 inhibitor, but it has two inherent structural limitations: (1) the labile ester moiety leads to its rapid hydrolysis to the inactive Pyr8 in vivo, and (2) the alkylating trichloroacrylic amide moiety is known to be toxic. To circumvent these limitations, we designed a series of conformationally restricted Pyr3 analogues and reported that compound 20 maintains high potency and selectivity for human TRPC3 over its closely related TRP channels. It has significantly improved metabolic stability compared with Pyr3 and has a good safety profile. Preliminary evaluation of 20 demonstrated its ability to rescue Aβ-induced neuron damage with similar potency to that of Pyr3 in vitro. Collectively, these results suggest that 20 represents a promising scaffold to potentially ameliorate the symptoms associated with TRPC3-mediated neurological and cardiovascular disorders.
Design, synthesis and biological evaluation of AZD9291 derivatives as selective and potent EGFRL858R/T790M inhibitors
Zhao, Bingbing,Xiao, Zhen,Qi, Jianguo,Luo, Rong,Lan, Zhou,Zhang, Yanzhuo,Hu, Xiaohan,Tang, Qidong,Zheng, Pengwu,Xu, Shan,Zhu, Wufu
, p. 367 - 380 (2018/12/13)
Third-generation epidermal growth factor receptor (EGFR)L858R/T790M inhibitors are still the main drugs for the treatment of advanced non-small cell lung cancer (NSCLC), and these drugs have achieved remarkable clinical efficacy. However, there are still many patients suffering from drug-resistant mutations and drug side effects caused by NSCLC. In this study, guided by the molecular simulation, we applied a structure-based drug design strategy (SBDD) and optimized the structure to obtain a series of potent and selective EGFRL858R/T790M inhibitors. The most potent compound 18e demonstrated excellent kinase inhibitory activity and selectivity for EGFRL858R/T790M double mutants and the IC50 value reached nanomolar level. The selectivity of 18e against wild-type EGFR was near to 200-fold. In addition, compound 18e also inhibited H1975 cells proliferation at G2/M phase and induced apoptosis at a concentration of 0.25 μM, which makes it more valuable for potential lung cancer research.
Synthesis of radioiodinated probes to evaluate the biodistribution of a potent TRPC3 inhibitor
Hagimori, Masayori,Murakami, Takahiro,Shimizu, Kinue,Nishida, Motohiro,Ohshima, Takashi,Mukai, Takahiro
supporting information, p. 1003 - 1006 (2016/06/08)
The transient receptor potential canonical 3 (TRPC3) channel is a member of the TRPC family that contributes to the entry of Ca2+ through the plasma membrane or modulates the driving force for Ca2+ entry channels. The pyrazole compound Pyr3 has recently been reported to be a selective TRPC3 inhibitor and has become an attractive research tool and therapeutic agent for the treatment of heart failure. However, the in vivo characteristics of Pyr3 have not been investigated. To monitor the fate of Pyr3 in vivo, we designed and synthesized a radioiodinated Pyr3 probe ([125I]I-Pyr3) by introducing radioiodine at the 2-position of the central phenyl ring of Pyr3. I-Pyr3 was shown to have direct TRPC3 inhibition activity similar to that of Pyr3 in TRPC3-overexpressing HEK293 cells. Using the tributyltin derivative as a radioiodination precursor, [125I]I-Pyr3 was successfully prepared with high radiochemical purity. Biodistribution studies of [125I]I-Pyr3 and [125I]I-Pyr8 (the esterolysis product of [125I]I-Pyr3) indicated high uptake of intact [125I]I-Pyr3 in the lung and rapid metabolism to [125I]I-Pyr8. These findings provide useful information about the in vivo kinetics of the selective TRPC inhibitor Pyr3.
Chemistry of polyhalogenated nitrobutadienes, 2: Synthesis of N-tetrachloroallylidene-N′-arylhydrazines by a formal synproportionation reaction
Zapol'skii, Viktor A.,Nutz, Eva,Namyslo, Jan C.,Adam, Arnold E. W.,Kaufmann, Dieter E.
, p. 2927 - 2933 (2008/02/05)
The reaction of 2-nitropentachlorobuta-1,3-diene with a variety of anilines substituted with electron-withdrawing groups generates, contrary to expectations, N-tetrachloroallylidene-N′-arylhydrazines instead of 1,1-bisaminated substitution products. The imidoyl-type chlorides are capable of undergoing nucleophilic substitution with amines or hydrides. The resulting compounds should exhibit physiological activity, especially for use in crop science. Georg Thieme Verlag Stuttgart.
Experimental study on the thermal oxidation of 1,3-hexachlorobutadiene at 500-1100°C
Baillet,Fadli,Sawerysyn
, p. 1261 - 1273 (2007/10/03)
Thermal degradation processes of 1,3-hexachlorobutadiene (C4Cl6) have been studied using a tubular flow reactor at 1 atm over the temperature range 500-1100°C for residence times of 2 seconds. Kinetic studies were performed with mixtures of 1000 ppmV of C4Cl6 in air. Overall Arrhenius parameters for the destruction of C4Cl6 were determined between 700 and 850°C. About 30 molecular halogenated products from C1 to C8 formed by pyrolysis or oxidation of 1,3-hexachlorobutadiene over the investigated temperature range were identified. Concentration profiles of major products (CO2, Cl2, CO, COCl2, C2Cl4, CCl4) and some minor products (C3Cl4O, C4Cl4O, C6Cl6, C3Cl4 and C3Cl6) have been measured as a function of temperature. Phosgene is the major chlorinated intermediate product. Detection of some aromatics such as hexachlorobenzene and octachlorostyrene show the importance of the molecular growth pathways in the chemical mechanism. Reaction pathways of main products are proposed and corresponding reaction enthalpies are estimated.
Synthesis of α-Halocinnamate Esters via Solvolytic Rearrangement of Trichloroallyl Alcohols
Kruper, William J.,Emmons, Albert H.
, p. 3323 - 3329 (2007/10/02)
Aryl trichlorovinyl ketones undergo regioselective reduction to the corresponding carbinols with sodium borohydride in alcoholic solvents and are transformed to the (Z)-α-chlorocinnamate ester derivatives via an acid-catalyzed allylic rearrangement.Micharl addition of ammonia to these ester derivatives affords cis- and/or trans-aziridine amides.The facile rearrangement allows the synthesis of d,l-phenylalanine derived from perchloroethylene and toluene.
