781649-09-0

Basic information

• Product Name: MK 0974, Telcagepant
• Synonyms: MK 0974, Telcagepant;Telcagepant;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)-1-piperidinecarboxamide;Mk 0974;Mk0974;Mk-0974;N-(6-(2,3-Difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl)-4-(2-oxo-2,3-dihydro-1H-imidazo(4,5-B)pyridin-1-yl)piperidine-1-carboxamide;MK0947
• CAS NO: 781649-09-0
• Molecular Formula: C₂₆H₂₇F₅N₆O₃
• Molecular Weight: 566.528
• Product Categories: API
• Mol File: 781649-09-0.mol
• Article Data: 7

Chemical Properties

• Appearance: /
• Density: 1.54
• Solubility: Soluble in DMSO
• PKA: 12.03±0.20(Predicted)
• CAS DataBase Reference: MK 0974, Telcagepant(CAS DataBase Reference)
• NIST Chemistry Reference: MK 0974, Telcagepant(781649-09-0)
• EPA Substance Registry System: MK 0974, Telcagepant(781649-09-0)

Safety Data

• Hazardous Substances Data: 781649-09-0(Hazardous Substances Data)

Usage

Biological Activity

mk-0974 (telcagepant) is a highly potent, selective, and orally bioavailable antagonist of cgrp receptor with ic50 value of 0.77 nm [1].calcitonin gene-related peptide (cgrp) receptor is a heteromeric transmembrane receptor composed of a g protein-coupled receptor which is called calcitonin receptor-like receptor (calcrl) and a receptor activity modifying protein 1 (ramp1). cgrp receptor is functional for mediating the activity of cgrp, which is widely distributed in human peripheral and central neuron system. the cgrp/cgrp receptor signaling pathway modulate a variety of physiological functions of respiratory, immune and cardiovascular system, and play a key role in the pathophysiology of migraine headache.when binding study was carried out, it was found mk-0974 had high affinity for cgrp receptor but had no affinity for related human adrenomedullin receptors, which suggested the high specificity of mk-0974 [1]. in human hek293 cells expressing cgrp receptor, treatment of mk-0974 resulted in potent blockage of α-cgrp-stimulated camp producation, which indicated a significant inhibition of cgrp receptor activity. however, addition of 50% human serum reduced the inhibition potency of mk-0974 by 5-fold [1]. mk-0974 displayed reversible and saturable binding to both sk-n-mc membranes and rhesus cerebellum with a kd of 1.9 nm and 1.3 nm, respectively [2].in rhesus model, capsaicin-induced release of endogenous cgrp resulted in dermal vasodilation. following treatment of mk-0974 produced a dose-dependent inhibition of dermal vasodilation, with plasma concentrations of 127 and 994 nm required to block 50 and 90% of the blood flow increase, respectively. the suppression of cgrp function indicated the inhibition of cgrp receptor by mk-0974 [1]. in monkey model, mk-0974 showed moderate clearance (14-20 ml min-1 kg-1), while oral bioavailability was 6%. the pharmacokinetics of mk-0974 remained linear across 0.5-10 mg kg-1 intravenous dose in monkeys, but the oral area under the plasma concentration-time curve (auc) increase (5-30 mg kg-1) was 15-fold over dose-proportional [3].

references

[1] salvatore c a et al. , pharmacological characterization of mk-0974 [n-[(3r,6s)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1h-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide], a potent and orally active calcitonin gene-related peptide receptor antagonist for the treatment of migraine. j pharmacol exp ther. 2008, 324(2): 416-421.[2] moore e l et al. , examining the binding properties of mk-0974: a cgrp receptor antagonist for the acute treatment of migraine. eur j pharmacol. 2009, 602(2-3): 250-254.[3]. roller s et al., preclinical pharmacokinetics of mk-0974, an orally active calcitonin-gene related peptide (cgrp)-receptor antagonist, mechanism of dose dependency and species differences. xenobiotica. 2009, 39(1): 33-45.

Upstream product

• 953081-45-3 C₁₈H₁₇F₅N₄O₂ 
• 781650-41-7 (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one 
• 7693-46-1 4-Nitrophenyl chloroformate 
• 530-62-1 1,1'-carbonyldiimidazole 
• 906532-82-9 4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylic acid ethyl ester 
• 906532-72-7 4-[1-(2-chloro-pyridin-3-yl)ureido]piperidine-1-carboxylic acid ethyl ester 
• 953077-37-7 (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)-azepan-2-one hydrochloride 

Relevant articles and documents

Process for the preparation of Caprolactam Cgrp Antagonist

An efficient syntheses for the preparation of (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one.

Potent, orally bioavailable calcitonin gene-related peptide receptor antagonists for the treatment of migraine: Discovery of N-(3R,6S)-6-(2,3- difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl-4-(2-oxo-2, 3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide (MK-0974)

Calcitonin gene-related peptide (CGRP) has been implicated in the pathogenesis of migraine. Herein we describe optimization of CGRP receptor antagonists based on an earlier lead structure containing a (3R)-amino-(6S)- phenylcaprolactam core. Replacement of the phenylimidazolinone with an azabenzimidazolone gave stable derivatives with lowered serum shifts. Extensive SAR studies of the C-6 aryl moiety revealed the potency-enhancing effect of the 2,3-difluorophenyl group, and trifluoroethylation of the N-1 amide position resulted in improved oral bioavailabilities, ultimately leading to clinical candidate 38 (MK-0974).

PROCESS FOR THE PREPARATION OF PYRIDINE HETEROCYCLE CGRP ANTAGONIST INTERMEDIATE

An efficient syntheses for the preparation of the intermediate 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine dihydrochloride, and other salt forms of 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine.