Abstract:
:Herein we continued our previous work on the development of CB2 ligands, reporting the design and synthesis of a series of benzimidazole-containing derivatives that were explored as selective CB2 ligands with binding affinity towards both CB1 and CB2 receptors. Seven out of eighteen compounds exhibited preferential binding ability to CB2 over CB1 receptors with potencies in the sub-micromolar or low micromolar range. In particular, we identified two promising hit compounds, the agonist 1-[2-(N,N-diethylamino)ethyl]-2-(4-ethoxybenzyl)-5-trifluoromethylbenzimidazole (3) (CB2: Ki = 0.42 μM) and the inverse agonist/antagonist 1-butyl-2-(3,4-dichlorobenzyl)-5-trifluoromethylbenzimidazole (11) (CB2: Ki = 0.37 μM). Docking studies also performed on other benzimidazoles reported in the literature supported the structure-activity relationship observed in this series of compounds and allowed the key contacts involved in the agonist and/or inverse agonist behaviour displayed by these derivatives to be determined. The in silico evaluation of ADMET properties suggested a favorable pharmacokinetic and safety profile, promoting the drug-likeness of these compounds towards a further optimization process.
journal_name
Medchemcommjournal_title
MedChemCommauthors
Tonelli M,Cichero E,Mahmoud AM,Rabbito A,Tasso B,Fossa P,Ligresti Adoi
10.1039/c8md00461gsubject
Has Abstractpub_date
2018-10-10 00:00:00pages
2045-2054issue
12eissn
2040-2503issn
2040-2511pii
c8md00461gjournal_volume
9pub_type
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