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, 8 (6), 1235-1245
eCollection

Pyrazolo[3,4- d]pyrimidines as sigma-1 Receptor Ligands for the Treatment of Pain. Part 1: 4-acylamino Derivatives

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Pyrazolo[3,4- d]pyrimidines as sigma-1 Receptor Ligands for the Treatment of Pain. Part 1: 4-acylamino Derivatives

José Luis Díaz et al. Medchemcomm.

Abstract

The synthesis of a new series of 4-acylaminopyrazolo[3,4-d]pyrimidines active on the sigma-1 receptor (σ1R) is reported. Compounds were efficiently prepared using a two to three step process starting from commercially available 1H-pyrazolo[3,4-d]pyrimidin-4-amine. A SAR study shows that the σ1R requires the presence of relatively highly lipophilic substituents at opposite sides of the central scaffold, while selectivity versus the σ2R can be improved by shortening the distance of the basic nitrogen to it. Compound 9a was among the most active and selective in vitro derivatives and exhibited potent antinociceptive properties in several pain models in mice, indicating its antagonistic behaviour.

Figures

Fig. 1
Fig. 1. General structure of pyrazolo[3,4-d]pyrimidines I and reference compound 1.
Scheme 1
Scheme 1. Reagents and conditions: (a) NaH, DMF, rt, 16 h; (b) K2CO3, NaI, DMF, rt, 16 h; (c) R3COCl, pyridine, TEA, DMAP, 130 °C, MW; (d) R3NCX, acetonitrile or toluene, 120–150 °C, MW.
Fig. 2
Fig. 2. Potential regioisomeric composition in the alkylation of 2.
Fig. 3
Fig. 3. Compounds 18 (ref. 21) and 19 (ref. 22).
Fig. 4
Fig. 4. (A) Main features of the Laggner σ1R pharmacophore in comparison to the distances described by the Glennon σ1R pharmacophore. (B) 3D superposition of 18 with Laggner σ1R pharmacophoric features. (C) 3D superposition of 9a and 18.
Fig. 5
Fig. 5. Compounds 4b and 20versus9a.

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