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.2009 Oct;4(10):1615-29.
doi: 10.1002/cmdc.200900226.

2,3-Dihydro-1-benzofuran derivatives as a series of potent selective cannabinoid receptor 2 agonists: design, synthesis, and binding mode prediction through ligand-steered modeling

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2,3-Dihydro-1-benzofuran derivatives as a series of potent selective cannabinoid receptor 2 agonists: design, synthesis, and binding mode prediction through ligand-steered modeling

Philippe Diaz et al. ChemMedChem.2009 Oct.

Abstract

We recently discovered and reported a series of N-alkyl-isatin acylhydrazone derivatives that are potent cannabinoid receptor 2 (CB(2)) agonists. In an effort to improve the druglike properties of these compounds and to better understand and improve the treatment of neuropathic pain, we designed and synthesized a new series of 2,3-dihydro-1-benzofuran derivatives bearing an asymmetric carbon atom that behave as potent selective CB(2) agonists. We used a multidisciplinary medicinal chemistry approach with binding mode prediction through ligand-steered modeling. Enantiomer separation and configuration assignment were carried out for the racemic mixture for the most selective compound, MDA7 (compound 18). It appeared that the S enantiomer, compound MDA104 (compound 33), was the active enantiomer. Compounds MDA42 (compound 19) and MDA39 (compound 30) were the most potent at CB(2). MDA42 was tested in a model of neuropathic pain and exhibited activity in the same range as that of MDA7. Preliminary ADMET studies for MDA7 were performed and did not reveal any problems.

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Figures

Figure 1
Figure 1
Structures of CB2-selective modulators1–6, a nonselective CB agonist7, and a CB1-selective antagonist8: 1 (AM1241),[105]2 (A-796260),[106]3 (GW842166X),[30]4 (CRA13),[40]5 (MDA19),[42]6 (A-83633),[43]7 (CP55,940),[107]8 (AM251).[108]
Figure 2
Figure 2
Comparison of the 3,3-disubstituted-2,3-dihydro-1-benzofuran scaffold with the isatin scaffold.
Figure 3
Figure 3
Compound33 with atom labeling shown.
Figure 4
Figure 4
A) CB2 complexed with compound33 (yellow carbon atoms). Transmembrane regions (TM) are shown as white ribbons; the image was prepared using PyMOL (http://www.pymol.org). B) A putative hydrogen bond between S3.31 and compound33 (yellow carbon atoms) is represented as red dashes. The aromatic pocket is enclosed by residues F5.46 and W6.48 (green carbon atoms).
Figure 5
Figure 5
Effects of A) compound1 and B) compound19 administered by intraperitoneal injection on tactile allodynia in a paclitaxel-induced neuropathic pain model in rats (n =5–6 per group). C) Compound19 dose-dependently attenuated tactile allodynia in this model, as evidenced by an increase in the percent MPE withdrawal threshold area under the curve (AUC);P <0.05 between the vehicle (V) and compound19 at 15 mg kg−1 (ANOVA followed by Tukey–Kramer test for multiple group comparison). Compound1 did not affect the paw withdrawal threshold. The effects of compound1, a CB2 ligand,[103] at 1, 3, and 5 mg kg−1 were not significantly different from the effects induced by the vehicle.
Scheme 1
Scheme 1
Reagents and conditions: a) K2CO3, methyl ethyl ketone, 3-bromo-2-methylpropene; b) K2CO3, [Pd(OAc)2],nBu4NCl, DMF, PhB(OH)2; c) NaOH, EtOH, THF, H2O; d) HATU, DiPEA, DMF, CH2Cl2, 2-iodoaniline for13 or cyclohexylamine for14 or piperidine for15.
Scheme 2
Scheme 2
Reagents and conditions: a) K2CO3, methyl ethyl ketone, 3-bromo-2-methylpropene; b) K2CO3, [Pd(OAc)2],nBu4NCl, DMF, PhB(OH)2 for11 b or 1-penten-1-ylboronic acid for11 c; c) NaOH, EtOH, THF, H2O; d) HATU, DiPEA, DMF, CH2Cl2, 2-iodoaniline for16 or cyclohexylamine for17 and20 or piperidine for18 and19 or neopentylamine for21 or morpholine for22 orN-tert-butylmethylamine for23 or 4-(aminomethyl)tetrahydropyran for24.
Scheme 3
Scheme 3
Reagents and conditions: a) NaOH, EtOH, THF, H2O; b) HATU, DiPEA, DMF, CH2Cl2, cyclohexylamine for26 a or piperidine for26 b; c) K2CO3, [Pd(OAc)2],nBu4NCl, DMF, 1-naphthylboronic acid for27 and28 or 2-naphthylboronic acid for29 or 4-chlorophenylboronic acid for30 or 4-methoxyboronic acid for31 or 4-pyridylboronic acid for32.
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