Discovery of (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)-1-oxopropan-2-yl)-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide (BMS-742413): A potent human CGRP antagonist with superior safety profile for the treatment of migraine through intranasal delivery

Chaturvedula, Prasad V.; Mercer, Stephen E.; Pin, Sokhom S.; Thalody, George; Xu, Cen; Conway, Charlie M.; Keavy, Deborah; Signor, Laura J.; Cantor, Glenn H.; Mathias, Neil; Moench, Paul; Denton, Rex; Macci, Robert; Schartman, Richard; Whiterock, Valerie J.; Davis, Carl D.; Macor, John E.; Dubowchik, Gene M.

doi:10.1016/j.bmcl.2013.04.012

Cited by 47 publications

(39 citation statements)

References 21 publications

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“…Continued exploration of PS structures as well as the amide portion of the antagonist led to vazegepant (36, BHV-3500, BMS-742413, Figure 16). 110 The combination of the oxidatively stable 2-quinolone PS replacement and the N-methylpiperidylpiperazine amide obviated both problems encountered with BMS-694153 while at the same time retaining excellent binding affinity (K i = 0.023 nM), aqueous solubility (>300 mg/mL below pH 8.5 from crystalline free base) and large free fraction (human f u = 37%). In the marmoset facial blood flow model, vazegepant (0.03 mg/kg, SC) demonstrated strong inhibition of CGRP-induced increases in facial blood flow at 15 (48%), 60 (80%), and 105 min (75%).…”

Section: ■ Second Generation Oral Compoundsmentioning

confidence: 99%

“…For comparison, small molecule antagonist values typically fall within 10-fold of one another (for rimegepant, binding K i = 0.027 nM, cAMP IC 50 = 0.14 nM; 118 for vazegepant, binding K i = 0.023 nM, cAMP IC 50 = 0.022 nM). 110 The three human CGRP ligand-binding antibodies are galcanezumab (Eli Lilly, LY 2951742, K D = 0.031 nM, IgG 4 ), 137 fremanezumab (Teva, TEV-48125, K D = 0.0022 nM, IgG 2 ), 138 and eptinezumab (ALD403, Alder, K D < 0.020 nM, IgG 2 ). 139 These effectively neutralize some portion of circulating hαCGRP ligand, preventing it from signaling through the CLR/RAMP1 receptor.…”

Section: ■ Antibodiesmentioning

confidence: 99%

“…Erenumab (AMG 334, IgG 1 ), discovered by a group at Amgen, binds to the human CLR/RAMP1 receptor with high affinity ( K i = 0.02 nM). , It is a functional antagonist, though it is interesting to note that its functional activity in blocking cAMP generation in the typical SK-N-MC cell assay (cAMP IC 50 = 2.3 nM) requires 100-fold higher concentrations vs simple binding. For comparison, small molecule antagonist values typically fall within 10-fold of one another (for rimegepant, binding K i = 0.027 nM, cAMP IC 50 = 0.14 nM; for vazegepant, binding K i = 0.023 nM, cAMP IC 50 = 0.022 nM) . The three human CGRP ligand-binding antibodies are galcanezumab (Eli Lilly, LY 2951742, K D = 0.031 nM, IgG 4 ), fremanezumab (Teva, TEV-48125, K D = 0.0022 nM, IgG 2 ), and eptinezumab (ALD403, Alder, K D < 0.020 nM, IgG 2 ) .…”

Section: Antibodiesmentioning

confidence: 99%

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Blocking the CGRP Pathway for Acute and Preventive Treatment of Migraine: The Evolution of Success

2020

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The pivotal role of calcitonin gene-related peptide (CGRP) in migraine pathophysiology was identified over 30 years ago, but the successful clinical development of targeted therapies has only recently been realized. This Perspective traces the decades long evolution of medicinal chemistry required to advance small molecule CGRP receptor antagonists, also called gepants, including the current clinical agents rimegepant, vazegepant, ubrogepant, and atogepant. Providing clinically effective blockade of CGRP signaling required surmounting multiple challenging hurdles, including defeating a sizable ligand with subnanomolar affinity for its receptor, designing antagonists with an extended confirmation and multiple pharmacophores while retaining solubility and oral bioavailability, and achieving circulating free plasma levels that provided near maximal CGRP receptor coverage. The clinical efficacy of oral and intranasal gepants and the injectable CGRP monoclonal antibodies (mAbs) are described, as are recent synthetic developments that have benefited from new structural biology data. The first oral gepant was recently approved and heralds a new era in the treatment of migraine.

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Section: ■ Second Generation Oral Compoundsmentioning

confidence: 99%

Section: ■ Antibodiesmentioning

confidence: 99%

Section: Antibodiesmentioning

confidence: 99%

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Blocking the CGRP Pathway for Acute and Preventive Treatment of Migraine: The Evolution of Success

2020

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“…The chemical properties of zavegepant make the product candidate potentially suitable for multiple routes of delivery, including nasal, subcutaneous, inhalation or oral administration. 47,48 This is the only CGRP antagonist undergoing clinical trials with both intranasal and oral formulations being developed for both acute treatment as well as prevention of migraine. In clinical trials, commonly reported adverse events are dysgeusia, nasal discomfort, but hepatotoxicity is not noticed.…”

Section: Zavegepant (Bhv-3500; Formerly Bms-742413)mentioning

confidence: 99%

Gepants, calcitonin gene-related peptide antagonists, for abortive treatment of migraine: current status

Gaddam

Padi

2021

Int J Basic Clin Pharmacol

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Migraine is a neurovascular disorder characterized by unilateral, recurrent, pulsating, throbbing, and moderate to severe headache. Triptans use is often limited by their poor efficacy, reports of poor responders, and contraindicated in patients with cardiovascular disorders. Calcitonin gene-related peptide (CGRP), a neuropeptide, regulates vascular tonicity as well as potent pain mediator, and both the mechanisms involved in development of migraine headache. Gepants are non-peptide, small molecules, highly selective, and potent CGRP antagonists. These novel drugs have been approved for abortive treatment of acute migraine with or without aura. These are being evaluated for their effectiveness and showing promising results in the prevention of migraine. Gepants do not have vasoconstrictive properties, are safe to use in patients with cardiovascular risk, and best alternative to triptan therapy. These are available in tablet, orally disintegrating tablet, and nasal forms to improve patient compliance. Ubrogepant and rimegepant are the two oral CGRP antagonists approved whereas atogepant and zavegepant are at late stage of development for approval.

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“…Based on the promising results achieved by previous phase II and phase III studies, novel anti-CGRP receptor compounds have been recently developed and investigated. New derivatives of telcagepant, MK-2918, have been explored (76) and an intranasal anti-CGRP receptor antagonist has been developed (BMS742413) (77). Future RCTs are needed in order to assess their efficacy and tolerability.…”

Section: Gepants Overallmentioning

confidence: 99%

CGRP – a target for acute therapy in migraine: Clinical data

Messina

Goadsby

2018

Cephalalgia

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Background A better understanding of the mechanisms underlying the migraine attack has reinforced the concept that migraine is a complex brain disease, and has paved the way for the development of new migraine specific acute treatments. In recent years, targeting the calcitonin gene-related peptide and its receptors has been one of the most promising pharmacological strategies for both acute and preventive treatment of migraine. Findings Randomized double-blind placebo-controlled trials have demonstrated the superiority of small molecule calcitonin gene-related peptide receptor antagonists (gepants) over placebo in treating acute migraine attacks measured as the two-hour pain free endpoint. Gepants also improved migraine associated symptoms, such as nausea, photophobia and phonophobia. Two of the class have had their development stopped because of hepatotoxicity, which is emerging as being due to metabolites. Gepants have a good tolerability and can be safely used in patients with stable cardiovascular disease. Conclusion Exciting results have been obtained targeting the calcitonin gene-related peptide pathway to abort acute migraine attacks, thus reinforcing the relevance of mechanism-based treatments specific for migraine.

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Discovery of (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)-1-oxopropan-2-yl)-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide (BMS-742413): A potent human CGRP antagonist with superior safety profile for the treatment of migraine through intranasal delivery

Cited by 47 publications

References 21 publications

Blocking the CGRP Pathway for Acute and Preventive Treatment of Migraine: The Evolution of Success

Blocking the CGRP Pathway for Acute and Preventive Treatment of Migraine: The Evolution of Success

Gepants, calcitonin gene-related peptide antagonists, for abortive treatment of migraine: current status

CGRP – a target for acute therapy in migraine: Clinical data

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