MK-0974 – All About Drugs

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Telcagepant, MK-0974

Molecular FormulaC₂₆H₂₇F₅N₆O₃
Average mass566.523 Da

1-piperidinecarboxamide, N-[(3R,6S)-6-(2,3-difluorophenyl)hexahydro-2-oxo-1-(2,2,2-trifluoroethyl)-1H-azepin-3-yl]-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-1-yl)-

CAS 781649-09-0

ChemSpider 2D Image | Telcagepant | C26H27F5N6O3

OriginatorMerck & Co
ClassAntimigraines; Piperidines
Mechanism of ActionCalcitonin gene-related peptide receptor antagonists

Migraine is a neurovascular disorder characterized by severe, debilitating, and throbbing unilateral headache. Though a leading cause of disability, it is a highly prevalent disease with a clear unmet medical need. With the significant progress achieved in the field of pathophysiology in the past decades, to date, it is well recognized that the neuropeptide calcitonin gene-related peptide (CGRP), which is expressed mainly in the central and peripheral nervous system, plays a crucial role in migraine. Antagonism of CGRP receptors, as a potential new therapy for the treatment of migraine, could offer the advantage of avoiding the cardiovascular liabilities associated with other existing antimigraine therapies.

Image result for Telcagepant

Telcagepant (INN) (code name MK-0974) is a calcitonin gene-related peptide receptor antagonist which was an investigational drug for the acute treatment and prevention of migraine, developed by Merck & Co. In the acute treatment of migraine, it was found to have equal potency to rizatriptan^[1] and zolmitriptan^[2] in two Phase III clinical trials. The company has now terminated development of the drug.

Mechanism of action

The calcitonin gene-related peptide (CGRP) is a strong vasodilator primarily found in nervous tissue. Since vasodilation in the brain is thought to be involved in the development of migraine and CGRP levels are increased during migraine attacks, this peptide may be an important target for potential new antimigraine drugs.

Telcagepant acts as a calcitonin gene-related peptide receptor (CRLR) antagonist and blocks this peptide. It is believed to constrict dilated blood vessels within the brain.^[3]

Termination of a clinical trial

A Phase IIa clinical trial studying telcagepant for the prophylaxis of episodic migraine was stopped on March 26, 2009 after the “identification of two patients with significant elevations in serum transaminases”.^[4] A memo to study locations stated that telcagepant had preliminarily been reported to increase the hepatic liver enzyme alanine transaminase (ALT) levels in “11 out of 660 randomized (double-blinded) study participants.” All study participants were told to stop taking the medication.^[5]

On July 29, 2011, it was reported that Merck & Co. were discontinuing the clinical development program for telcagepant. According to Merck, “[t]he decision is based on an assessment of data across the clinical program, including findings from a recently completed six-month Phase III study”.^[6]

CLIP

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CLIP

Image result for telcagepant

CLIP

Asymmetric Synthesis of Telcagepant

http://pubs.acs.org/doi/abs/10.1021/jo101704b

Abstract Image

As part of the process of bringing a new API to market, it is often required to use an alternative synthetic strategy to the initial medicinal chemistry approach. Here Xu et al. of Merck Rahway disclose their efforts towards an improved multikilogram synthesis of telcagepant, a CGRP receptor antagonist for the treatment of migraines ( J. Org. Chem. 2010, 75, 7829−7841). The route described in the report is an example of a synthetic target driving the discovery of new chemistries.

Of note are the challenges they faced and overcame in particular the asymmetric Michael addition of nitromethane to a cinnamyl aldehyde. Initial attempts under Hayashi’s conditions gave promising results (50−75% yield) and moreover confirmed a high enantioselectivity could be achieved using the Jorgensen−Hayashi catalyst. However, the use of benzoic acid as the acidic cocatalyst gave rise to undesired byproducts. After performing a comprehensive screen of conditions Xu showed that the combination of the weak acids t-BuCO₂H (5 mol %) and B(OH)₃(50 mol %) minimized the level of impurities. Of specific note is that this is the first reported application of iminium organocatalysis on industrial scale.

The second milestone achieved in the strategy was the prevention of the protodefluorination under hydrogenative conditions. During the initial studies between 1.06−2.5% of the desfluoro compounds were formed by using Pd(OH)₂/C in 100% conversion. To suppress the by product formation Xu screened a range of inorganic additives and found that 0.3 eq of LiCl gave a reproducible reaction where less than 0.2% of the desfluoro compounds were generated.

telcagepant as its crystalline potassium salt ethanol solvate in 92% yield with >99.9% purity and >99.9% ee.

¹H NMR (400 MHz, d₄-MeOH): δ 7.75 (dd, J = 5.3, 1.4 Hz, 1 H), 7.38 (dd, J = 7.6, 1.4 Hz, 1 H), 7.15 (m, 3 H), 6.70 (dd, J = 7.6, 5.3 Hz, 1 H), 4.85 (d, J = 11.4 Hz, 1 H), 4.55 (m, 1 H), 4.45 (dq, J = 15.4, 9.5 Hz, 1 H), 4.27 (m, 3 H), 4.05 (dq, J = 15.4, 9.0 Hz, 1 H), 3.61 (q, J = 7.1 Hz, 2 H), 3.46 (d, J = 15.4 Hz, 1 H), 3.16 (m, 1 H), 3.0 (m, 2 H), 2.42 (dq, J = 12.7, 4.4 Hz, 1 H), 2.27 (dq, J = 12.7, 4.4 Hz, 1 H), 2.16 (m, 3 H), 1.81 (m, 3 H). 1.18 (t, J = 7.1 Hz, 3 H).

¹³C NMR (100 MHz, d₄-MeOH): δ 176.8, 166.1, 159.3, 157.4, 152.1 (dd, J = 246.8, 13.6 Hz), 149.4 (dd, J = 245.1, 13.1 Hz), 139.2, 134.7 (d, J = 11.9 Hz), 127.7, 126.3 (q, J = 279.7 Hz), 126.2 (dd, J = 7.1, 4.8 Hz), 124.3 (t, J = 3.4 Hz), 116.8 (d, J = 17.1 Hz), 114.5, 113.8, 58.5, 55.3, 55.2, 51.6, 49.9 (q, J = 33.6 Hz), 45.4, 45.3, 39.8, 35.9, 32.7, 30.74, 30.72, 18.5.

References

Jump up^ Ho, Tw; Mannix, Lk; Fan, X; Assaid, C; Furtek, C; Jones, Cj; Lines, Cr; Rapoport, Am; Mk-0974, Protocol, 004, Study, Group (Apr 2008). “Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine”. Neurology. 70 (16): 1304–12. doi:10.1212/01.WNL.0000286940.29755.61. PMID 17914062.
Jump up^ Ho TW, Ferrari MD, Dodick DW, et al. (December 2008). “Efficacy and tolerability of MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, compared with zolmitriptan for acute migraine: a randomised, placebo-controlled, parallel-treatment trial”. Lancet. 372 (9656): 2115–23. doi:10.1016/S0140-6736(08)61626-8. PMID 19036425.
Jump up^ Molecule of the Month February 2009
Jump up^ Clinical trial number NCT00797667 for “MK0974 for Migraine Prophylaxis in Patients With Episodic Migraine” at ClinicalTrials.gov
Jump up^ Merck & Co.: Memo to all US study locations involved in protocol MK0974-049
Jump up^ Merck Announces Second Quarter 2011 Financial Results

Telcagepant
Clinical data


Routes of administration	Oral
ATC code	none
Legal status
Legal status	Development terminated
Pharmacokinetic data
Biological half-life	5–8 hours
Identifiers
IUPAC name [show]
CAS Number	781649-09-0
PubChem (CID)	11319053
IUPHAR/BPS	703
ChemSpider	9494017
UNII	D42O649ALL
KEGG	D09391
ChEMBL	CHEMBL236593
Chemical and physical data
Formula	C₂₆H₂₇F₅N₆O₃
Molar mass	566.5283 g/mol
3D model (Jmol)	Interactive image

1 to 10 of 14

Patent ID	Patent Title	Submitted Date	Granted Date
US7534784	CGRP receptor antagonists	2008-11-13	2009-05-19
US7452903	CGRP receptor antagonists	2007-09-27	2008-11-18
US7235545	CGRP receptor antagonists	2005-11-17	2007-06-26
US6953790	CGRP receptor antagonists	2004-11-18	2005-10-11

Patent ID	Patent Title	Submitted Date	Granted Date
US8394767	Methods of treating cancer using the calcitonin-gene related peptide (â??CGRPâ??) receptor antagonist CGRP8-37	2011-01-10	2013-03-12
US8080544	PRODRUGS OF CGRP RECEPTOR ANTAGONISTS	2010-11-25	2011-12-20
US7893052	CGRP RECEPTOR ANTAGONISTS	2010-11-25	2011-02-22
US2010286122	CGRP Antagonist Salt	2010-11-11
US7829699	Process for the Preparation of Cgrp Antagonist	2009-11-12	2010-11-09
US7772224	CGRP RECEPTOR ANTAGONISTS	2009-07-30	2010-08-10
US7745427	Cgrp Receptor Antagonists	2008-04-17	2010-06-29
US7718796	Process for the preparation of Caprolactam Cgrp Antagonist	2009-05-14	2010-05-18
US2010009967	SOLID DOSAGE FORMULATIONS OF TELCAGEPANT POTASSIUM	2010-01-14
US2009176986	Process for the Preparation of Pyridine Heterocycle Cgrp Antagonist Intermediate	2009-07-09

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent