153472-86-7Relevant articles and documents
An exit beyond the pharmacophore model for 5-HT6R agents - a new strategy to gain dual 5-HT6/5-HT2A action for triazine derivatives with procognitive potential
?es?awska, Ewa,Agnieszka-Olejarz-Maciej,Ali, Wesam,Czarnota, Kinga,Handzlik, Jadwiga,Jastrz?bska-Wi?sek, Magdalena,Kucwaj-Brysz, Katarzyna,Kurczab, Rafa?,Latacz, Gniewomir,Mordyl, Barbara,Nitek, Wojciech,Partyka, Anna,Sata?a, Grzegorz,Sudo?-Ta?aj, Sylwia,Weso?owska, Anna,Wilczyńska-Zawal, Natalia
, (2022/03/01)
This research allowed us to find the first highly potent 5-HT6/5-HT2A receptor (5-HT6/5-HT2AR) dual antagonists in a group of 1,3,5-triazine compounds as a result of an exit beyond the hydrophobic feature of the pharmacophore model for 5-HT6R antagonists. Design and synthesis of the series (2–16) of new O- and S-containing ether derivatives of 1,3,5-triazines with the double-ring aromatic region have been performed. The new compounds were examined within the comprehensive pharmacological screening, including: radioligand binding assays, functional and ADMET studies in vitro as well as behavioral tests in rats. Crystallographic aspects and computer-aided structure–activity relationship were analyzed, as well. The comprehensive approach led to selection of compound 12 (4-(4-methylpiperazin-1-yl)-6-(2-(naphthalen-2-ylthio)propan-2-yl)-1,3,5-triazin-2-amine) with the most significant dual 5-HT6/5-HT2AR antagonistic action (5-HT6R Ki = 11 nM, 5-HT2AR Ki = 39 nM). Moreover, the compound 12 has satisfactory ADMETox properties in vitro, i.e.: the high permeability through biological membranes, high metabolic stability, neither mutagenic nor hepatotoxic effects, and moderate ability to inhibit CYP3A4. Above all, 12 showed ability to reverse the pharmacologically-induced (MK-801) memory impairment at low doses (1–3 mg/kg) in Novel Object Recognition (NOR) test in rats. Our results indicate a promising potency of dual 5-HT6/5-HT2AR antagonism in the search for novel strategy to fight Alzheimer's disease, which remains an unmet clinical need.
Optical resolution of aryloxypropionic acids and their esters by HPLC on cellulose tris-3,5-dimethyl-triphenylcarbamate derivative
Azzolina,Collina,Ghislandi
, p. 1401 - 1416 (2007/10/02)
Chiral chromatographic resolution of a series of antiphlogistic 2- aryloxypropionic acids and their methyl and ethyl esters was performed using a Chiralcel OD column. The CSP selected resolved most of the acids and esters efficiently, the enantiomers being well separated without requiring time consuming analysis. Chromatographic separation of R enriched samples was performed to determine the correct elution order. Using eluting systems such as hexane and 2-propanol, or hexane, 2-propanol and formic acid, the S enantiomer of all acids and esters was always found to elute first. We also considered the role of electron-donating or electron-withdrawing substituents (at the aryloxylic moiety) on the chiral resolution. It was shown that the electronic features of the substituents have more influence on the chiral interactions between the solutes and the CSP than their steric hindrance. Finally we determined, by molecular models, the interaction between CSP and solutes. In this way were able to determine all the potential sites for interactions, which are compatible with the conformations of the compounds and the structure of the stationary phase, and point out those interactions which enable chiral resolution.
