39103-38-3Relevant articles and documents
A Simple Synthesis of Chromones
Hercouet, A.,Le Corre, M.,Le Floc'h, Y.
, p. 597 - 598 (1982)
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2-Styrylchromone derivatives as potent and selective monoamine oxidase B inhibitors
Takao, Koichi,Endo, Saki,Nagai, Junko,Kamauchi, Hitoshi,Takemura, Yuri,Uesawa, Yoshihiro,Sugita, Yoshiaki
, (2019/09/30)
A series of eighteen 2-styrylchromone derivatives (see Chart 1) were synthesized and evaluated for their monoamine oxidase (MAO) A and B inhibitory activities. Many of the derivatives inhibited MAO-B comparable to pargyline (a positive control), and most of them inhibited MAO-B selectively. Of the eighteen derivatives, compound 9 having methoxy group at R1 and chlorine at R4 showed both the best MAO-B inhibitory activity (IC50 = 17 ± 2.4 nM) and the best MAO-B selectivity (IC50 for MAO-A/IC50 for MAO-B = 1500). The mode of inhibition of compound 9 against MAO-B was competitive and reversible. Quantitative structure–activity relationship (QSAR) analyses of the 2-styrylchromone derivatives were conducted using their pIC50 values with the use of Molecular Operating Environment (MOE) and Dragon, demonstrating that the descriptors of MAO-B inhibitory activity and MAO-B selectivity were 1734 and 121, respectively, that showed significant correlations (P 50 value indexes for MAO-B exhibited a determination coefficient (R2) of 0.873 as well as a Leave-One-Out cross-validated determination coefficient (Q2) of 0.675. These data suggested that the 2-styrylchromone structure might be a useful scaffold for the design and development of novel MAO-B inhibitors.
Discovery, Structure-Activity Relationship, and Antiparkinsonian Effect of a Potent and Brain-Penetrant Chemical Series of Positive Allosteric Modulators of Metabotropic Glutamate Receptor 4
Charvin, Delphine,Pomel, Vincent,Ortiz, Millan,Frauli, Mélanie,Scheffler, Sophie,Steinberg, Edith,Baron, Luc,Deshons, Laurène,Rudigier, Rachel,Thiarc, Delphine,Morice, Christophe,Manteau, Baptiste,Mayer, Stanislas,Graham, Danielle,Giethlen, Bruno,Brugger, Nadia,Hédou, Ga?l,Conquet, Fran?ois,Schann, Stephan
, p. 8515 - 8537 (2017/11/03)
The metabotropic glutamate receptor 4 (mGluR4) is an emerging target for the treatment of Parkinson's disease (PD). However, since the discovery of its therapeutic potential, no ligand has been successfully developed enough to be tested in the clinic. In the present paper, we report for the first time the medicinal chemistry efforts conducted around the pharmacological tool (-)-PHCCC. This work led to the identification of compound 40, a potent and selective mGluR4 positive allosteric modulator (PAM) with good water solubility and demonstrating consistent activity across validated preclinical rodent models of PD motor symptoms after intraperitoneal administration: haloperidol-induced catalepsy in mouse and the rat 6-hydroxydopamine (6-OHDA) lesion model. Moreover, we also describe the identification of compound 60 a close analogue of compound 40 with improved pharmacokinetic profile after oral administration. On the basis of its favorable and unique preclinical profile, compound 60 (PXT002331, now foliglurax) was nominated as a candidate for clinical development.