Novel Potent 5-HT_(1F) Receptor Agonists: Structure-Activity Studies of a Series of Substituted N-[3-(1-Methyl-4-piperidinyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]amides

摘要

Compound 1a (LY334370), a selective 5-HT_(1F) receptor agonist (SSOFRA), inhibited dural inflammation in the neurogenic plasma protein extravasation model of migraine and demonstrated clinical efficacy for the acute treatment of migraine. Although 1a was greater than 100-fold selective over both the 5-HT_(1B) and 5-HT_(1D) receptors, it exhibited appreciable 5-HT_(1A) receptor affinity. Described here is the synthesis and evaluation of a series of pyrrolo-[2,3-c]pyridine and pyrrolo[3,2-b]pyridine (2a and 3a) as well as pyrrolo[3,2-d]pyrimidine (4a) analogues of 1a, compounds prepared in an effort to identify SSOFRAs with improved selectivity over other 5-HT_1 receptor subtypes. The pyrrolo[3,2-b]pyridine analogue 3a showed high 5-HT_(1F) receptor affinity but offered no improvement in selectivity compared to 1a. However, the C-5 acetamide derivative, 3b, was greater than 100-fold selective over the 5-HT_(1A), 5-HT_(1B), and 5-HT_(1D) receptors. SAR studies of this series determined that alkylamides in particular exhibited high selectivity for the 5-HT_(1F) receptor. Replacement at C-5 with other substituents decreased affinity or selectivity. These SAR studies identified SSOFRAs that demonstrated oral activity in the neurogenic plasma protein extravasation model, a model indicative of antimigraine activity.