Discovery of (5S,6S,9R)-5-Amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (BMS-927711): An Oral Calcitonin Gene-Related Peptide (CGRP) Antagonist in Clinical Trials for Treating Migraine

Luo, Guanglin; Chen, Ling; Conway, Charles M.; Denton, Rex; Keavy, Deborah; Signor, Laura J.; Kostich, Walter; Lentz, Kimberley A.; Santone, Kenneth S.; Schartman, Richard; Browning, Marc; Tong, Gary; Houston, John G.; Dubowchik, Gene M.; Macor, John E.

doi:10.1021/jm3013147

Cited by 73 publications

(76 citation statements)

References 19 publications

(47 reference statements)

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“…However, as for MK0974 (Merck & Co., 21 April ), MK3207 development was stopped due to the asymptomatic liver toxicity detected in some of the enrolled patients (Edvinsson and Linde, ). The development of both the oral CGRP antagonist, BI 44370 TA, which has been found superior to placebo end equieffective to eletriptan (Diener et al ., ), and the orally bioavailable antagonist, BMS‐927711 (Luo et al ., ) has been stopped (Dolgin, ).…”

Section: Calcitonin Gene‐related Peptide (Cgrp) and Migrainementioning

confidence: 99%

The TRPA1 channel in migraine mechanism and treatment

Benemei

Fusi

Trevisan

et al. 2014

British J Pharmacology

126

108

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Migraine remains an elusive and poorly understood disease. The uncertainty is reflected by the currently unsatisfactory acute and prophylactic treatments for this disease. Genetic and pharmacological information points to the involvement of some transient receptor potential (TRP) channels in pain mechanisms. In particular, the TRP vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1) channels seem to play a major role in different models of pain diseases. Recent findings have underscored the possibility that TRP channels expressed in the nerve terminals of peptidergic nociceptors contribute to the migraine mechanism. Among this channel subset, TRPA1, a sensor of oxidative, nitrative and electrophilic stress, is activated by an unprecedented series of irritant and pain-provoking exogenous and endogenous agents, which release the pro-migraine peptide, calcitonin gene-related peptide, through this neuronal pathway. Some of the recently identified TRPA1 activators have long been known as migraine triggers. Furthermore, specific analgesic and antimigraine medicines have been shown to inhibit or desensitize TRPA1 channels. Thus, TRPA1 is emerging as a major contributing pathway in migraine and as a novel target for the development of drugs for pain and migraine treatment. LINKED ARTICLESThis article is part of a themed section on the pharmacology of TRP channels. To view the other articles in this section visit http://dx

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Section: Calcitonin Gene‐related Peptide (Cgrp) and Migrainementioning

confidence: 99%

The TRPA1 channel in migraine mechanism and treatment

Benemei

Fusi

Trevisan

et al. 2014

British J Pharmacology

126

108

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“…, ; Luo et al . , ). There is unlikely to be a single reason why there are currently no CGRP receptor antagonists available for migraine treatment or management.…”

Section: Introductionmentioning

confidence: 97%

“…However, elevated transaminase levels in a few patients with longer-term treatment apparently halted the progression of this compound. Other CGRP receptor antagonists, such as MK-3207, BI-44370 and BMS-927711, have reached clinical trials but less is known about these molecules (Diener et al, 2011;Hewitt et al, 2011;Luo et al, 2012). There is unlikely to be a single reason why there are currently no CGRP receptor antagonists available for migraine treatment or management.…”

Section: Introductionmentioning

confidence: 99%

CGRP in the trigeminovascular system: a role for CGRP, adrenomedullin and amylin receptors?

Walker

Hay

2013

British J Pharmacology

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The neuropeptide calcitonin gene-related peptide (CGRP) is reported to play an important role in migraine. It is expressed throughout the trigeminovascular system. Antagonists targeting the CGRP receptor have been developed and have shown efficacy in clinical trials for migraine. However, no CGRP antagonist is yet approved for treating this condition. The molecular composition of the CGRP receptor is unusual because it comprises two subunits; one is a GPCR, the calcitonin receptor-like receptor (CLR). This associates with receptor activity-modifying protein (RAMP) 1 to yield a functional receptor for CGRP. However, RAMP1 also associates with the calcitonin receptor, creating a receptor for the related peptide amylin but this also has high affinity for CGRP. Other combinations of CLR or the calcitonin receptor with RAMPs can also generate receptors that are responsive to CGRP. CGRP potentially modulates an array of signal transduction pathways downstream of activation of these receptors, in a cell type-dependent manner. The physiological significance of these signalling processes remains unclear but may be a potential avenue for refining drug design. This complexity has prompted us to review the signalling and expression of CGRP and related receptors in the trigeminovascular system. This reveals that more than one CGRP responsive receptor may be expressed in key parts of this system and that further work is required to determine their contribution to CGRP physiology and pathophysiology. LINKED ARTICLES

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“…Rimegepant (BHV-3000; formerly BMS-927711) is a small molecule drug that has recently been approved as a treatment for migraine (Scott, 2020). It is a member of the "gepant" class of molecules which antagonize the activity of the neuropeptide calcitonin gene-related peptide (CGRP) (Luo et al, 2012;Hargreaves and Olesen, 2019). CGRP is a key player in migraine (Hargreaves and Olesen, 2019).…”

Section: Introductionmentioning

confidence: 99%

Antagonism of CGRP Signaling by Rimegepant at Two Receptors

et al. 2020

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The "gepants" are a class of calcitonin gene-related peptide (CGRP) receptor antagonist molecules that have been developed for the prevention and treatment of migraine. Rimegepant is reported to act at the CGRP receptor, has good oral bioavailability, and has had positive clinical trial results. However, there is very little data available describing its receptor pharmacology. Importantly, rimegepant activity at the AMY 1 receptor, a second potent CGRP receptor that is known to be expressed in the trigeminovascular system, has not been reported. The ability of rimegepant to antagonize activation of human CGRP, AMY 1 , and related adrenomedullin receptors was determined in transfected in Cos7 cells. Rimegepant was an effective antagonist at both the CGRP and AMY 1 receptor. The antagonism of both CGRP and AMY 1 receptors may have implications for our understanding of the mechanism of action of rimegepant in the treatment of migraine.

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Discovery of (5S,6S,9R)-5-Amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (BMS-927711): An Oral Calcitonin Gene-Related Peptide (CGRP) Antagonist in Clinical Trials for Treating Migraine

Cited by 73 publications

References 19 publications

The TRPA1 channel in migraine mechanism and treatment

The TRPA1 channel in migraine mechanism and treatment

CGRP in the trigeminovascular system: a role for CGRP, adrenomedullin and amylin receptors?

Antagonism of CGRP Signaling by Rimegepant at Two Receptors

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