618070-60-3Relevant 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.
Pyrtriazoles, a Novel Class of Store-Operated Calcium Entry Modulators: Discovery, Biological Profiling, and in Vivo Proof-of-Concept Efficacy in Acute Pancreatitis
Riva, Beatrice,Griglio, Alessia,Serafini, Marta,Cordero-Sanchez, Celia,Aprile, Silvio,Di Paola, Rosanna,Gugliandolo, Enrico,Alansary, Dalia,Biocotino, Isabella,Lim, Dmitry,Grosa, Giorgio,Galli, Ubaldina,Niemeyer, Barbara,Sorba, Giovanni,Canonico, Pier Luigi,Cuzzocrea, Salvatore,Genazzani, Armando A.,Pirali, Tracey
, p. 9756 - 9783 (2018/11/23)
In recent years, channels that mediate store-operated calcium entry (SOCE, i.e., the ability of cells to sense a decrease in endoplasmic reticulum luminal calcium and induce calcium entry across the plasma membrane) have been associated with a number of d
MODULATORS OF SOCE, COMPOSITIONS, AND USES THEREOF
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Page/Page column 44, (2018/01/19)
Compounds of Formula (I) able to modulate Store Operated Calcium Entry (SOCE). The disclosure also relates to the use of compounds of formula (I) for treatment of pathological conditions in which SOCE modulation might be beneficial, such as neglecting dis
Microwave-assisted and continuous flow multistep synthesis of 4-(pyrazol-1-yl)carboxanilides
Obermayer, David,Glasnov, Toma N.,Kappe, C. Oliver
experimental part, p. 6657 - 6669 (2011/10/18)
A series of 4-(pyrazol-1-yl)carboxanilides active as inhibitors of canonical transient receptor potential channels were synthesized in an efficient three-step protocol using controlled microwave heating. The general synthetic strategy involves condensation of 4-nitrophenylhydrazine with appropriate 1,3-dicarbonyl building blocks, followed by reduction of the nitro group to the amine, which is then amidated with carboxylic acids. Compared to the conventional protocol a dramatic reduction in overall processing time from ～2 days to a few minutes was achieved, accompanied by significantly improved product yields. In addition, the first two steps in the synthetic pathway were also performed under continuous flow conditions providing similar isolated product yields. As an alternative to the three-step protocol, a novel two-step route to the desired 4-(pyrazol-1-yl)carboxanilides was devised involving condensation of 4-bromophenylhydrazine with appropriate 1,3-dicarbonyl building blocks, followed by Pd-catalyzed Buchwald-Hartwig amidation with carboxylic acid amides.
