Design, synthesis, and binding mode prediction of 2-pyridone-based selective CB2 receptor agonists

^a Medicinal Research Laboratories, Shionogi Pharmaceutical Research Center, 11-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan
^b Faculty of Pharmacy, Chiba Institute of Science, 15-8 Shiomi-cho, Choshi, Chiba 288-0025, Japan

Abstract

Selective CB2 agonists have the potential for treating pain without central CB1-mediated adverse effects. Screening efforts identified 1,2-dihydro-3-isoquinolone 1; however, this compound has the drawbacks of being difficult to synthesize with two asymmetric carbons on an isoquinolone scaffold and of having a highly lipophilic physicochemical property. To address these two major problems, we designed the 2-pyridone-based lead 15a, which showed moderate affinity for CB2. Optimization of 15a led to identification of 39f with high affinity for CB2 and selectivity over CB1. Prediction of the binding mode of 39f in complex with an active-state CB2 homology model provided structural insights into its high affinity for CB2.

Graphical abstract

: Figure options

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InChIKey

IPCYPXCGYWGJEK-UHFFFAOYSA-N

Abbreviations

cAMP, 3′,5′-cyclic adenosine monophosphate;
CB, cannabinoid;
CHO, Chinese hamster ovary;
CNS,central nervous system;
DCM, dichloromethane;
DMF, N,N-dimethylformamide;
DPPA,diphenylphosphonic azide;
ECL, extracellular loop;
ESI, electrospray ionization;
LRMS, low-resolution mass spectrometry;
Pd/C, palladium on carbon;
SAR, structure–activity relationship;
THC,tetrahydrocannabinol;
TLC, thin layer chromatography

Keywords

Cannabinoid;
CB2;
Agonist;
Pyridone;
Pyridine-2-one;
Homology model

Figures and tables from this article:

: Figure 1. Screening hit 1.; Figure options

: Figure 2. Structural design of 2-pyridone scaffold from 1,2-dihydro-3-isoquinolone.; Figure options

: Figure 3. Docking of 39f into the CB2 homology model. Key residues are depicted. (a) Binding pocket viewed from the extracellular surface. The hydrogen bond is shown as dotted lines. (b) Side view with extracellular side at the top. (c) Diagram of 39f in the binding pocket. Hydrophobic interactions are shown as red lines and the hydrogen bond is shown as dotted lines.; Figure options

: Scheme 1. Reagents and conditions: (a) BnNH₂, toluene, reflux; (b) 2-methoxyacetyl chloride, pyridine, Et₂O, 0 °C to rt; (c) Na, EtOH–toluene, reflux; (d) 5-chloro-1-phenyl-1H-tetrazole, K₂CO₃, DMF, rt; (e) 10% Pd/C, H₂ (5 kg/cm²), DMF, rt; (f) n-BuI, NaOH, 1-butanol, 85 °C; (g) pyridinium chloride, 200 °C; (h) 2-chlorobenzo[d]oxazole, NaH, DMF, rt.; Figure options

: Scheme 2. Reagents and conditions: (a) R-I, NaOH, 1-butanol, 85 °C; (b) Lawesson’s reagent, toluene, reflux; (c) pyridinium chloride, 200 °C; (d) 2-chlorobenzo[d]oxazole, NaH, DMF, rt.; Figure options

: Scheme 3. Reagents and conditions: (a) n-BuI, NaH, DMF; (b) Lawesson’s reagent, toluene, reflux; (c) pyridinium chloride, 200 °C; (d) 2-chlorobenzo[d]oxazole, NaH, DMF, rt; (e) N,N,N′,N′-tetramethylmethylenediamine, EtOH–H₂O, 75 °C; (f) (i) MeI, DCM, rt, (ii) PPh₃, EtOH, 75 °C, (iii) aq NaOH, MeOH, 60 °C; (g) 2-chlorobenzo[d]oxazole, NaH, DMF, rt.; Figure options

: Scheme 4. Reagents and conditions: (a) N,N,N′,N′-tetramethylmethylenediamine, EtOH–H₂O, 75 °C; (b) (i) MeI, DCM rt, (ii) PPh₃, EtOH, 75 °C, (iii) aq NaOH, MeOH, 60 °C; (c) n-BuI, NaH, DMF, rt; (d) Lawesson’s reagent, toluene, reflux; (e) pyridinium chloride, 165 °C; (f) 2-chlorobenzo[d]oxazole, NaH, DMF, rt.; Figure options

: Scheme 5. Reagents and conditions: (a) n-BuNH₂, rt; (b) 2-methyl-3-oxobutanal sodium salt, piperidine, AcOH, DMF, 135 °C; (c) KOH, 80% aq EtOH, reflux, 85%; (d) DPPA, Et₃N, BnOH, dioxane, 110 °C; (e) 10% Pd/C, MeOH, rt; (f) R³COCl, pyridine, THF, rt.; Figure options