Guy Rosalia Eugene Van Lommen

The discovery of a series of new non-indole 5HT1D agonists

Abstract The synthesis and SAR of a series of non-indole 5HT1D agonists is described. The most interesting molecule of this series is compound 13, alniditan. It is active as a constrictor of the saphenous vein of the dog and of the pig basilar artery with ED50 values of 9.09×10−9M and 2.29×10−8M respectively, and it has high affinities to the 5HT1D-receptor and to the 5HT1D-receptor with pKi values of 8.6 and 8.3 respectively.

5-sulfonyl-benzimidazoles as selective CB2 agonists-part 2.

In a previous communication, the SAR of a series of potent and selective 5-sulfonyl-benzimidazole CB2-receptor agonists was described. The lack of in vivo activity of compounds from this series was attributed to their poor solubility and metabolic stability. In this Letter, we report on the further optimization of this series, leading to the relatively polar and peripherically acting CB2 agonists 41 and 49. Although both compounds were not active in acute pain models, the less selective compound 41 displayed good, sustained activity in a chronic model of neuropathic pain without the tolerance observed with morphine. In addition, both 41 and 49 delayed the onset of clinical symptoms in an experimental model for Multiple sclerosis.