Yao-Chang Xu

Preclinical pharmacological profile of the selective 5-HT1F receptor agonist lasmiditan

Introduction: Lasmiditan (also known as COL-144 and LY573144; 2,4,6-trifluoro-N-[6-[(1-methylpiperidin-4-yl)carbonyl]pyridin-2yl]benzamide) is a high-affinity, highly selective serotonin (5-HT) 5-HT1F receptor agonist. Results: In vitro binding studies show a Ki value of 2.21 nM at the 5-HT1F receptor, compared with Ki values of 1043 nM and 1357 nM at the 5-HT1B and 5-HT1D receptors, respectively, a selectivity ratio greater than 470-fold. Lasmiditan showed higher selectivity for the 5-HT1F receptor relative to other 5-HT1 receptor subtypes than the first generation 5-HT1F receptor agonist LY334370. Unlike the 5-HT1B/1D receptor agonist sumatriptan, lasmiditan did not contract rabbit saphenous vein rings, a surrogate assay for human coronary artery constriction, at concentrations up to 100 µM. In two rodent models of migraine, oral administration of lasmiditan potently inhibited markers associated with electrical stimulation of the trigeminal ganglion (dural plasma protein extravasation, and induction of the immediate early gene c-Fos in the trigeminal nucleus caudalis). Conclusions: Lasmiditan presents a unique pyridinoyl-piperidine scaffold not found in any other antimigraine class. Its chemical structure and pharmacological profile clearly distinguish it from the triptans. The potency and selectivity of lasmiditan make it ideally suited to definitively test the involvement of 5-HT1F receptors in migraine headache therapy.

Selective deprotection of esters using magnesium and methanol

Abstract The use of magnesium metal in methanol for the deprotection of alkyl esters is described. This mild reagent also provides good to excellent selectivity to cleave different esters. The order of the reactivity of this reagent towards acyl cleavages was found to be: p-nitrobenzoate > acetate > benzoate > pivaloate > trifluroacetamide.

Discovery of selective N-[3-(1-methyl-piperidine-4-carbonyl)-phenyl]-benzamide-based 5-HT1F receptor agonists: Evolution from bicyclic to monocyclic cores

Preclinical experiments and clinical observations suggest the potential effectiveness of selective 5-HT1F receptor agonists in migraine. Identifying compounds with enhanced selectivity is crucial to assess its therapeutic value. Replacement of the indole nucleus in 2 (LY334370) with a monocyclic phenyl ketone moiety generated potent and more selective 5-HT1F receptor agonists. Focused SAR studies around this central phenyl ring demonstrated that the electrostatic and steric interactions of the substituent with both the amide CONH group and the ketone CO group play pivotal roles in affecting the adopted conformation and thus the 5-HT1F receptor selectivity. Computational studies confirmed the observed results and provide a useful tool in the understanding of the conformational requirements for 5-HT1F receptor agonist activity and selectivity. Through this effort, the 2-F-phenyl and N-2-pyridyl series were also identified as potent and selective 5-HT1F receptor agonists.