Please login first
A Practical Access to New Pyrazole SKF-96365 Analogues as Potential Store-Operated Calcium Entry (SOCE) Inhibitors
* 1 , 2, 3 , 4 , 5 , 6 , 3 , 3 , 7
1  Institut des Sciences Chimiques de Rennes, ISCR UMR 6226, groupe CORINT, Université de Rennes 1, Bât. 10A, Campus de Beaulieu, 263 Av. du Gén. Leclerc, CS 74205, 35042 Rennes Cedex (France)
2  Université de Nangui Abrogoua
3  Laboratoire de Chimie Bio Organique et de Substances Naturelles (LCBOSN), Université Nangui Abrogoua (UNA), BP 802, Abidjan, Côte d'Ivoire
4  Institut des Sciences Chimiques de Rennes (ISCR), UMR CNRS 6226, groupe CORINT, Université de Rennes 1 (UR1), Campus de Beaulieu, Bât. 10A, 263 Avenue du Général Leclerc, CS 74205, 35042 Rennes Cedex, France
5  Institut des Sciences Chimiques de Rennes (ISCR), UMR CNRS 6226, Centre de Diffractométrie X (cdifx), Université de Rennes 1 (UR1), Campus de Beaulieu, Bât. 10B, 263 Avenue du Général Leclerc, CS 74205, 35042 Rennes Cedex, France
6  CalciScreen platform, Université de Bretagne Occidentale (UBO), 22 Avenue Camille Desmoulins, 29200 Brest Cedex, France
7  Laboratoire Canalopathies & Signalisation Calcique, Inserm U1227, Université de Bretagne Occidentale (UBO), 22 Avenue Camille Desmoulins, 29200 Brest Cedex, France

Published: 03 November 2018 by MDPI in 4th International Electronic Conference on Medicinal Chemistry session ECMC-4
Abstract:

The racemic synthesis in four steps of pyrazole SKF-96365 analogues without substituent (CF3 group) on the pyrazole platform was realized in moderate to good yields. The separation of (±) hydroxyl enantiomers 4 was developed successfully using the method of "half-concentration" with commercial (+)-(1S)- and (-)-(1R)-10-camphorsulfonic acid (CSA) followed by neutralization of diastereomers with MeONa in dry MeOH solution. With the pure enantiomers (-)-(1S)-4b and (+)-(1R)-4b, initial attempts to obtain the crystallized (-)-(1S)-7d and (+)-(1R)-7d after treatment of intermediate 6d with a solution of 1M HCl (for precipitation of hydrochloride salt 7d) failed. We have also investigated the effects of compounds 7(a-d) on endoplasmic reticulum (ER) Ca2+ and SOCE on PLP-B lymphocyte cell line and compound 7d was identified as a better SOCE inhibitor than SKF-96365. This preliminary SAR study showed that the MeO group in para-position of the phenethyl-1H-pyrazolium skeleton or for the Cbeta-phenylpropoxy side chain of 7 influenced the SOCE activity.

Keywords: pyrazole / SKF-96365 analogues / resolution / half-quantities / SOCE inhibitor / B lymphocyte cell / Ca2+ signalling
Top