MK-3207

Biological Activity

MK-3207 is a potent and orally bioavailable CGRP receptor antagonist (IC₅₀= 0.12 nM; K_i= 0.024 nM); highly selective versus human AM1, AM2, CTR, and AMY3. IC50 Value: 0.024 nM (Ki, Human CGRP) In common with other CGRP receptor antagonists, MK-3207 displays lower affinity for human CGRP receptors from other species, including canine and rodent. in vitro: MK-3207 is a potent antagonist of the human and rhesus monkey CGRP receptors (K(i) = 0.024 nM). in vivo: MK-3207 produced a concentration-dependent inhibition of dermal vasodilation, with plasma concentrations of 0.8 and 7 nM required to block 50 and 90% of the blood flow increase, respectively. The tritiated analog [3H]MK-3207 was used to study the binding characteristics on the human CGRP receptor. [3H]MK-3207 displayed reversible and saturable binding (K(D) = 0.06 nM), and the off-rate was determined to be 0.012 min(-1), with a t(1/2) value of 59 min. After the first interim analysis, the two lowest MK-3207 doses (2.5, 5 mg) were identified as showing insufficient efficacy. Per the pre-specified adaptive design decision rule, only the 2.5-mg group was discontinued and the five highest doses (5, 10, 20, 50, 100 mg) were continued into the second stage. Clinical trial: MK-3207 for the treatment of acute migraines. Phase 2b

Chemical Information

Molecular Weight	557.59
CAS Number	957118-49-9
Solubility (25°C)	DMSO ≥ 100 mg/mL
Storage	2-8°C, sealed

Conversion of different model animals based on BSA (PMID: 27057123)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.

References

[1] Richard Hargreaves, et al. Calcitonin Gene-Related Peptide Modulators - The History and Renaissance of a New Migraine Drug Class

[2] Chi-Chung Li, et al. Characterizing the PK/PD relationship for inhibition of capsaicin-induced dermal vasodilatation by MK-3207, an oral calcitonin gene related peptide receptor antagonist

[3] Ian M Bell, et al. Discovery of MK-3207: A Highly Potent, Orally Bioavailable CGRP Receptor Antagonist

[4] David J Hewitt, et al. Randomized controlled trial of the CGRP receptor antagonist MK-3207 in the acute treatment of migraine

[5] Christopher A Salvatore, et al. Pharmacological properties of MK-3207, a potent and orally active calcitonin gene-related peptide receptor antagonist