Molecule

Description

Cancer

Description

MK 3207 is a potent CGRP receptor antagonist with IC50 of 0.12 nM.

Targets

IC₅₀

In Vitro

MK 3207 exhibits significantly higher affinity for both native and recombinant human CGRP receptor, as well as rhesus monkey CGRP receptor with K_i of 24 pM, ~24 pM and 22 pM, respectively, as compared to CGRP receptors from other species, including canine and rodent (K_i values of ~10 nM). Although has affinity for AMY1 (CTR/RAMP1) receptor with a K_i value of 0.75 nM, MK 3207 displays marked selectivity for human CGRP receptor versus related human AM₁ (CLR/RAMP2) receptor, AM₂ (CLR/RAMP3) receptor, AMY3 (CTR/RAMP3) receptor, and CTR with K_i values of 16.5 μM, 0.156 μM, 0.128 μM and 1.9 μM, respectively. MK 3207 potently inhibits human α-CGRP-induced cAMP production in HEK293 cells stably expressing human CLR/RAMP1 with an IC50 of 0.12 nM, and maintains similar potency in the presence of 50% human serum with an IC50 of 0.17 nM, indicating that the activity of MK 3207 would not be dramatically affected by plasma protein binding in vivo. MK 3207 exhibits approximately 65-fold more potent in the human serum-shifted in vitro functional assay than telcagepant with an IC50 of 10.9 nM. ^[1]

In Vivo

Administration of MK 3207 produces a concentration-dependent inhibition of capsaicin-induced dermal vasodilation in rhesus monkeys, blocking the blood flow increase with an EC50 of 0.8 nM and an EC90 of 7 nM, respectively. MK 3207 displays approximately 100-fold more potent in the rhesus monkey CIDV assay versus telcagepant with an EC90 of 994 nM. ^[1]

Clinical Trials

A Phase II study to demonstrate the effectiveness and appropriate dosage level of MK 3207 in the treatment of acute migraine has been completed.

Features

MK 3207 is the most potent orally active CGRP receptor antagonist described to date.

In Vitro Functional Study

HEK293 cells stably expressing the human CGRP receptor are preincubated with various concentrations of MK 3207 in the presence or absence of 50% human serum for 30 minutes at 37 °C. Isobutyl-methylxanthine (300 μM) is added to the cells, and then they are incubated for 30 minutes at 37 °C followed by stimulation with 0.3 nM α-CGRP for 5 minutes at 37 °C. After agonist stimulation cells are washed with PBS and the intracellular cAMP concentration is measured using the cAMP SPA Biotrak direct screening assay. Dose-response curve is plotted, and IC50 value is determined.

Animal Models

Adult rhesus monkeys (either sex) with capsaicin-induced dermal vasodilation

Formulation

Dissolved in DMSO

Doses

~123.1 μg/kg

Administration

Intravenous bolus followed by 25 minutes continuous intravenous infusion