Discovery of (R)-4-(8-Fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl)piperidine-1-carboxamide (BMS-694153): A Potent Antagonist of the Human Calcitonin Gene-Related Peptide Receptor for Migraine with Rapid and Efficient Intranasal Exposure

Degnan, Andrew P.; Chaturvedula, Prasad V.; Conway, Charles M.; Cook, Deborah A.; Davis, Carl D.; Denton, Rex; Han, Xiaojun; Macci, Robert; Mathias, Neil; Moench, Paul; Pin, Sokhom S.; Ren, Shelly X.; Schartman, Richard; Signor, Laura J.; Thalody, George; Widmann, Kimberly A.; Xu, Cen; Macor, John E.; Dubowchik, Gene M.

doi:10.1021/jm800546t

Cited by 56 publications

(57 citation statements)

References 23 publications

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“…Therefore, can the AMY1 receptor be completely ruled out in terms of contributing to the actions of CGRP in migraine? Although other factors, such as the antagonist free fraction and target accessibility should be considered, it will be interesting to see how effectively a more CGRP receptor specific antagonist, such as BMS-694153, alleviates migraine (Degnan et al, 2008). How alternative CGRP blocking strategies, using CGRP binding entities, such as antibodies which act peripherally or RNA-spiegelmers behave when translated into the clinic will also provide valuable information and help define a peripheral versus central site of action (Edvinsson et al, 2007;Olesen and Ashina, 2011).…”

Section: Figurementioning

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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Section: Figurementioning

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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“…Bristol–Myers Squibb generated BMS‐694153 (Figure 1) which has high affinity for the human ( K i = 13 pM) CGRP receptor. BMS‐694153 did not exhibit significant oral bioavailability in monkey or rat and no clinical data are published for this compound (Degnan et al ., 2008).…”

Section: Discovery Of Cgrp Receptor Antagonistsmentioning

confidence: 99%

“…MK‐3207 is structurally distinct from telcagepant but nonetheless displays approximately 400‐fold higher affinity for the human and rhesus CGRP receptors compared with the rat and dog receptors (Salvatore et al ., 2010). Bristol–Myers Squibb generated BMS‐694153 (Figure 1), which has high affinity for the human and marmoset CGRP receptor, but was inactive on the rat receptor up to 1 µM (Degnan et al ., 2008).…”

Section: Species Selectivity Of Cgrp Receptor Antagonists – the Role mentioning

confidence: 99%

Targeting a family B GPCR/RAMP receptor complex: CGRP receptor antagonists and migraine

Moore

Salvatore

2012

British J Pharmacology

104

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The clinical effectiveness of antagonizing the calcitonin gene-related peptide (CGRP) receptor for relief of migraine pain has been clearly demonstrated, but the road to the development of these small molecule antagonists has been daunting. The key hurdle that needed to be overcome was the CGRP receptor itself. The vast majority of the current antagonists recognize similar epitopes on the calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1). RAMP1 is a relatively small, single, transmembrane-spanning protein and along with the G-protein-coupled receptor CLR comprise a functional CGRP receptor. The tri-helical extracellular domain of RAMP1 plays a key role in the high affinity binding of CGRP receptor antagonists and drives their species-selective pharmacology. Over the years, a significant amount of mutagenesis data has been generated to identify specific amino acids or regions within CLR and RAMP1 that are critical to antagonist binding and has directed attention to the CLR/RAMP1 extracellular domain (ECD) complex. Recently, the crystal structure of the CGRP receptor ECD has been elucidated and not only reinforces the early mutagenesis data, but provides critical insight into the molecular mechanism of CGRP receptor antagonism. This review will highlight the drug design hurdles that must be overcome to meet the desired potency, selectivity and pharmacokinetic profile while retaining drug-like properties. Although the development of these antagonists has proved challenging, blocking the CGRP receptor may one day represent a new way to manage migraine and offer hope to migraine sufferers.

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“…However, not all species among laboratory animals can reflect the distribution of CGRP receptors in humans. Only marmoset and rhesus monkeys have been found to show a human-like CGRP receptor pharmacology [154] [158]. The human CGRP receptor contains in its heteromeric RAMP1 structure a specific a.a.r.…”

Section: Cgrp Receptor Ligandsmentioning

confidence: 99%

Neuropeptide Receptors in Pain Circuitries: Useful Targets for CNS Imaging with Non-Peptide Ligands Suitable for PET?

Pissarek¹

2014

WJNS

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Cited by 56 publications

References 23 publications

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

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

Targeting a family B GPCR/RAMP receptor complex: CGRP receptor antagonists and migraine

Neuropeptide Receptors in Pain Circuitries: Useful Targets for CNS Imaging with Non-Peptide Ligands Suitable for PET?

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