MK-3207

MK-3207 is a new, highly selective CGRP receptor antagonist that is approximately 40- to 65-fold more potent than telcagepant for the human CGRP receptor. The IC50 is 0.12 nM and The Ki value is 0.024 nM. It is highly selective versus human AM1, AM2, CTR, and AMY3. [1]
Calcitonin gene-related peptide (CGRP) is a 37 amino acid neuropeptide that is widely distributed in the central and peripheral nervous system. The CGRP receptor is composed of the calcitonin receptor-like receptor (CLR), a family B G protein-coupled receptor (GPCR), in association with receptor activity modifying protein 1 (RAMP1) and receptor component protein. A number of lines of evidence implicated CGRP in migraine pathophysiology, and this led to interest in the potential utility of CGRP receptor antagonists as novel therapeutics for migraine. [2]
MK-3207 displayed high affinity for the native human CGRP receptor in SK-N-MC cells and for the recombinant human receptor as measured by the ability to compete with 125I-hCGRP binding, with Ki values of 0.024 ± 0.001 nM and 0.022 ± 0.002 nM, respectively. MK-3207 displayed a similar affinity (Ki) for the rhesus monkey receptor (0.024 ± 0.001 nM) as for human, but it displayed 400-fold lower affinity for the canine and rat receptors, with values of 10 nM and 10 ± 1.2 nM , respectively. MK-3207 potently blocked human α-CGRP-stimulated cAMP responses in human CGRP receptor-expressing HEK293 cells, with an IC50 value of 0.12 ±0.02 nM . Addition of 50% human serum (IC50 =0.17 ± 0.02nM) had little effect on the apparent potency ofMK-3207. [3]
MK-3207 has EC50 and Emax values of approximately 0.8 ± 0.3 nM (mean ± S.E.) and 81 ± 5% (mean ± S.E.), respectively, for inhibition of CIDV in rhesus monkeys. The expected EC90 value in rhesus monkey is therefore approximately 7 nM (9-fold higher than the estimated EC50 value). After an oral dose of 10 mg/kg MK-3207, the CSF/plasma ratio is 2 to 3% . However, the CSF/ plasma ratio is approximately 30% of the unbound fraction (9.4%) in plasma, indicating that the central and peripheral compartments are not freely equilibrating.

References:
[1] David J Hewitt, Sheena K Aurora, David W Dodick et al. Randomized controlled trial of the CGRP receptor antagonist MK-3207 in the acute treatment of migraine. Cephalalgia 31(6) 712–722.
[2] Ian M. Bell, Steven N. Gallicchio, Michael R. Wood et al. Discovery of MK-3207: A Highly Potent, Orally Bioavailable CGRP Receptor Antagonist. ACS Med. Chem. Lett. 2010, 1, 24–29.
[3] Christopher A. Salvatore, Eric L. Moore, Amy Calamari, Jacquelynn J. Cook, et al. Pharmacological Properties of MK-3207, a Potent and Orally Active Calcitonin Gene-Related Peptide Receptor Antagonist. doi:10.1124/jpet.109.163816.

Discovery of MK-3207: A Highly Potent, Orally Bioavailable CGRP Receptor Antagonist.[Pubmed:24900170]

ACS Med Chem Lett. 2010 Jan 12;1(1):24-9.

Incorporation of polar functionality into a series of highly potent calcitonin gene-related peptide (CGRP) receptor antagonists was explored in an effort to improve pharmacokinetics. This strategy identified piperazinone analogues that possessed improved solubility at acidic pH and increased oral bioavailability in monkeys. Further optimization led to the discovery of the clinical candidate 2-[(8R)-8-(3,5-difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(2R)-2'-oxo -1,1',2',3-tetrahydrospiro[indene-2,3'-pyrrolo[2,3-b]pyridin]-5-yl]acetamide (MK-3207) (4), the most potent orally active CGRP receptor antagonist described to date.

Characterizing the PK/PD relationship for inhibition of capsaicin-induced dermal vasodilatation by MK-3207, an oral calcitonin gene related peptide receptor antagonist.[Pubmed:25377933]

Br J Clin Pharmacol. 2015 May;79(5):831-7.

AIMS: Calcitonin gene related peptide (CGRP) receptor antagonists are effective acute migraine treatments. A capsaicin-induced dermal vasodilatation (CIDV) model has been developed to provide target-engagement information in healthy volunteers. In the model, CGRP release is provoked after dermal capsaicin application, by activating transient receptor potential vanilloid-type-1 (TRPV1) receptors at peripheral sensory nerves. Laser Doppler imaging is used to quantify CIDV and subsequent inhibition by CGRP receptor antagonists. We sought to evaluate a CGRP receptor antagonist, MK-3207, in the biomarker model and to assess the predictability of the CIDV response to migraine clinical efficacy. METHODS: An integrated population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the exposure-response relationship for CIDV inhibition by CGRP and TRPV1 receptor antagonists. MK-3207 dose-response predictions were made based on estimated potency from the PK/PD model and mean plasma concentrations observed at the doses investigated. RESULTS: The results suggested that a 20 mg dose of MK-3207 (EC50 of 1.59 nm) would be required to attain the peripheral CIDV response at a target level that was shown previously to correlate with 2 h clinical efficacy based on phase 3 telcagepant clinical data, and that a plateau of the dose-response would be reached around 40-100 mg. These predictions provided a quantitative rationale for dose selection in a phase 2 clinical trial of MK-3207 and helped with interpretation of the efficacy results from the trial. CONCLUSIONS: The integrated CIDV PK/PD model provides a useful platform for characterization of PK/PD relationships and predictions of dose-response relationships to aid in future development of CGRP and TRPV1 receptor antagonists.

Pharmacological properties of MK-3207, a potent and orally active calcitonin gene-related peptide receptor antagonist.[Pubmed:20065019]

J Pharmacol Exp Ther. 2010 Apr;333(1):152-60.

Calcitonin gene-related peptide (CGRP) has long been hypothesized to play a key role in migraine pathophysiology, and the advent of small-molecule antagonists has clearly demonstrated a clinical link between blocking the CGRP receptor and migraine efficacy. 2-[(8R)-8-(3,5-Difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(2R)-2'-oxo -1,1',2',3-tetrahydrospiro[indene-2,3'-pyrrolo[2,3-b]pyridin]-5-yl]acetamide (MK-3207) represents the third CGRP receptor antagonist to display clinical efficacy in migraine trials. Here, we report the pharmacological characterization of MK-3207, a potent and orally bioavailable CGRP receptor antagonist. In vitro, MK-3207 is a potent antagonist of the human and rhesus monkey CGRP receptors (K(i) = 0.024 nM). In common with other CGRP receptor antagonists, MK-3207 displays lower affinity for CGRP receptors from other species, including canine and rodent. As a consequence of species selectivity, the in vivo potency was assessed in a rhesus monkey pharmacodynamic assay measuring capsaicin-induced changes in forearm dermal blood flow via laser Doppler imaging. 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. In vitro autoradiography studies on rhesus monkey brain slices identified the highest level of binding in the cerebellum, brainstem, and meninges. Finally, as an index of central nervous system penetrability, the in vivo cerebrospinal fluid/plasma ratio was determined to be 2 to 3% in cisterna magna-ported rhesus monkeys.

Randomized controlled trial of the CGRP receptor antagonist MK-3207 in the acute treatment of migraine.[Pubmed:21383045]

Cephalalgia. 2011 Apr;31(6):712-22.

BACKGROUND: This study evaluated the CGRP receptor antagonist MK-3207 for acute treatment of migraine. METHODS: Multicenter, double-blind, randomized, placebo-controlled, parallel-group, two-stage adaptive study with two interim efficacy analyses to facilitate optimal dose selection. Migraine patients were initially randomized to MK-3207 2.5, 5, 10, 20, 50 and 100 mg or placebo to treat a moderate/severe migraine. One or more doses were to be discontinued based on the first interim analysis and a lower or higher dose could be added based on the second interim analysis. The primary endpoint was two-hour pain freedom. RESULTS: A total of 547 patients took study medication. 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. After the second interim efficacy analysis, a 200 mg dose was added due to insufficient efficacy at the top three (20, 50, 100 mg) doses. A positive dose-response trend was demonstrated when data were combined across all MK-3207 doses for two-hour pain freedom (p < .001). The pairwise difference versus placebo for two-hour pain freedom was significant for 200 mg (p < .001) and nominally significant for 100 mg and 10 mg (p < .05). The incidence of adverse events appeared comparable between active treatment groups and placebo, and did not appear to increase with increasing dose. CONCLUSIONS: MK-3207 was effective and generally well tolerated in the acute treatment of migraine.

MK-3207 is a potent and orally bioavailable CGRP receptor antagonist (IC50= 0.12 nM; Ki value= 0.024 nM); highly selective versus human AM1, AM2, CTR, and AMY3.

MK-3207,957118-49-9,Natural Products,CGRP, buy MK-3207 , MK-3207 supplier , purchase MK-3207 , MK-3207 cost , MK-3207 manufacturer , order MK-3207 , high purity MK-3207