Telcagepant

Telcagepant (MK-0974) is an orally active calcitonin gene-related peptide (CGRP) receptor antagonist with K_is of 0.77 nM and 1.2 nM for human and rhesus CGRP receptors, respectively. IC50 & Target: Ki: 0.77 nM (human CGRP), 1.2 nM (rhesus CGRP) In Vitro: Telcagepant (MK-0974) displays affinity (K_i) for the canine and rat receptors, with values of 1204 nM and 1192 nM (n=10), respectively. Telcagepant (MK-0974) potently blocks human α-CGRP-stimulated cAMP responses in human CGRP receptor expressing HEK293 cells with an IC₅₀ of 2.2 nM^[1]. Telcagepant (MK-0974) displays saturable binding to SK-N-MC membranes with a K_D of 1.9 nM and B_max of 479 fmol/mg protein. Telcagepant (MK-0974) also displays saturable binding to rhesus cerebellum homogenate with a K_D of 1.3 nM and B_max of 20 fmol/mg^[2]. In Vivo: Telcagepant (MK-0974) (i.v. bolus, 1 mg/kg) demonstrates that the efficacy of this antagonist is time-dependent and correlated with plasma levels^[1]. The pharmacokinetics of Telcagepant (MK-0974) remains linear across 0.5-10 mg/kg intravenous dose in monkeys, but the oral area under the plasma concentration-time curve (AUC) increase (5-30 mg/kg) is 15-fold over dose-proportional^[3].