Development of fluorinated and methoxylated benzothiazole derivatives as highly potent and selective cannabinoid CB2 receptor ligands

• Published in: Bioorganic chemistry Vol. 114; pp. 105191 - 105204
• Main Authors: Aly, Mayar W., Ludwig, Friedrich-Alexander, Deuther-Conrad, Winnie, Brust, Peter, Abadi, Ashraf H., Moldovan, Rareş-Petru, Osman, Noha A.
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.09.2021; Elsevier
• Subjects: Benzothiazole; Biochemistry & Molecular Biology; Cannabinoid receptor type 2; CB2 ligands; Chemistry; Chemistry, Organic; Fluorine; Life Sciences & Biomedicine; Metabolic studies; PET; Physical Sciences; Science & Technology; NADPH; rt; Fluorine; DMSO; SAR; Benzothiazole; TLC; SI; IC50; CDCl3; EC50; DMF; HPLC; EtOAc; Metabolic studies; MS; Et3N; eq; CB2 ligands; DCM; CB2; CB1; Cannabinoid receptor type 2; MeOH; PET; Ki; TYPE-2 RECEPTOR; ENDOCANNABINOID SYSTEM; HIGH-AFFINITY; PET TRACERS; DISCOVERY; IN-VITRO; MODELS; INDOLE; AGONISTS DESIGN; BINDING
• ISSN: 0045-2068; 1090-2120; 1090-2120
• DOI: 10.1016/j.bioorg.2021.105191

[Display omitted] •Synthesis of fluorinated and methoxylated benzothiazole derivatives.•Biological evaluation of compounds for their hCB1 and hCB2 binding affinity.•Identification of extremely potent and selective CB2 receptor ligands.•In vitro metabolic studies of 15 and 21 reveal the superior stability of 21 in HLM.•21 emerges as a credible lead that can be further exploited for radiolabeling. The upregulation of the CB2 receptors in neuroinflammation and cancer and their potential visualization with PET (positron emission tomography) could provide a valuable diagnostic and therapy-monitoring tool in such disorders. However, the availability of reliable CB2-selective imaging probes is still lacking in clinical practice. We have recently identified a benzothiazole-2-ylidine amide hit (6a) as a highly potent CB2 ligand. With the aim of enhancing its CB2 over CB1 selectivity and introducing structural sites suitable for radiolabeling, we herein describe the development of fluorinated and methoxylated benzothiazole derivatives endowed with extremely high CB2 binding affinity and an exclusive selectivity to the CB2 receptor. Compounds 14, 15, 18, 19, 21, 24 and 25 displayed subnanomolar CB2Ki values (ranging from 0.16 nM to 0.68 nM) and interestingly, all of the synthesized compounds completely lacked affinity at the CB1 receptor (Ki > 10,000 nM for all compounds), indicating their remarkably high CB2 over CB1 selectivity factors. The fluorinated analogs, 15 and 21, were evaluated for their in vitro metabolic stability in mouse and human liver microsomes (MLM and HLM). Both 15 and 21 displayed an exceptionally high stability (98% and 91% intact compounds, respectively) after 60 min incubation with MLM. Contrastingly, a 5- and 2.8-fold lower stability was demonstrated for compounds 15 and 21, respectively, upon incubation with HLM for 60 min. Taken together, our data present extremely potent and selective CB2 ligands as credible leads that can be further exploited for 18F- or 11C-radiolabeling and utilization as PET tracers.