129722-34-5Relevant articles and documents
Novel Bivalent Ligands Based on the Sumanirole Pharmacophore Reveal Dopamine D2 Receptor (D2R) Biased Agonism
Bonifazi, Alessandro,Yano, Hideaki,Ellenberger, Michael P.,Muller, Ludovic,Kumar, Vivek,Zou, Mu-Fa,Cai, Ning Sheng,Guerrero, Adrian M.,Woods, Amina S.,Shi, Lei,Newman, Amy Hauck
, p. 2890 - 2907 (2017)
The development of bivalent ligands has attracted interest as a way to potentially improve the selectivity and/or affinity for a specific receptor subtype. The ability to bind two distinct receptor binding sites simultaneously can allow the selective activation of specific G-protein dependent or β-arrestin-mediated cascade pathways. Herein, we developed an extended SAR study using sumanirole (1) as the primary pharmacophore. We found that substitutions in the N-1- and/or N-5-positions, physiochemical properties of those substituents, and secondary aromatic pharmacophores can enhance agonist efficacy for the cAMP inhibition mediated by Gi/o-proteins, while reducing or suppressing potency and efficacy toward β-arrestin recruitment. Compound 19 was identified as a new lead for its selective D2 G-protein biased agonism with an EC50 in the subnanomolar range. Structure-activity correlations were observed between substitutions in positions N-1 and/or N-5 of 1 and the capacity of the new bivalent compounds to selectively activate G-proteins versus β-arrestin recruitment in D2R-BRET functional assays.
Synthesis method of high-purity aripiprazole and preparation method of hydrate particles of aripiprazole
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Paragraph 0026; 0053; 0117-0130, (2021/08/07)
The invention discloses a synthesis method of high-purity aripiprazole and a preparation method of hydrate particles of aripiprazole. The method comprises the following steps: step (1), carrying out Williamson etherification on 7-hydroxyl-3,4-dihydro-2 (1H)-quinolinone and 1,4-dibromobutane under the action of potassium carbonate to obtain 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone; step (2), synthesizing 2,3-dichlorophenyl piperazine hydrochloride from 2,3-dichloroaniline and bis(2-chloroethyl) amine hydrochloride; step (3), carrying out an alkylation coupling reaction of nitrogen on 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone and 1-(2,3-dichlorophenyl) piperazine hydrochloride, so as to prepare aripiprazole; (4) refining: recrystallizing aripiprazole by using ethyl acetate to obtain high-purity anhydrous aripiprazole; and (5) preparation of aripiprazole hydrate particles: refluxing and dissolving anhydrous aripiprazole in an ethanol-water system, and controlling the stirring rate and the cooling rate to obtain the aripiprazole hydrate particles.
The one-pot synthesis of butyl-1H-indol-3-alkylcarboxylic acid derivatives in ionic liquid as potent dual-acting agent for management of BPH
Chen, Kaixuan,Jiang, Zhenzhou,Liu, Shuwen,Xi, Baomin,Yang, Fubiao,Zeng, Li-Yan,Zeng, Yunong
, (2020/09/18)
Based on the SAR of both α1-AR antagonists and 5α-reductase (5AR) inhibitors, the dual-acting agent 4-(1-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-1H-indol-3-yl)butanoic acid 4aaa was designed against BPH and synthesized by two steps of N-alkylation. One-pot protocol towards 4aaa was newly developed. With IL [C6min]Br as solvent, the yield of 4aaa was increased to 75.1% from 16.0% and the reaction time was shortened in 1.5 h from 48 h. 25 derivatives structurally based on arylpiperazine and indolyl butyric acid with alkyl linker were prepared. The protocol was futher extended to get another 14 derivatives wherein O-alkylation was involved, and applied to the synthesis of biologically efficient molecules DPQ and Aripiprazole. Expectedly, compound 4aaa exhibited dual inhibition of α1-AR and 5α-reductase, and exhibited no obvious cytotoxicity against human cells. The pharmacokinetic properties of 4aaa was also determined.