Development of Human Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonists. 1. Potent and Selective Small Molecule CGRP Antagonists. 1-[N2-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1- piperidinyl]carbonyl]-d-tyrosyl]-l-lysyl]-4-(4-pyridinyl)piperazine:  The First CGRP Antagonist for Clinical Trials in Acute Migraine†

Abstract Background: The pathophysiology of migraine has been researched incessantly, and it has been suggested that calcitonin gene-related peptide (CGRP) is associated with migraine attacks. CGRP receptor blockers are attracting attention for migraine prevention and treatment of acute episodes, and CGRP receptor antagonists have been shown to be effective in treating acute migraine headaches. This meta-analysis aimed to assess the effect of available CGRP receptor antagonists, focusing on their therapeutic doses for acute migraine treatment.Methods: We performed a systematic search of MEDLINE (from inception to March 2021) and EMBASE (from inception to March 2021) for English publications using the keywords “migraine” and “Calcitonin gene-related peptide,” limited to human studies.Results: Five studies that focused on examining the effects of CGRP receptor antagonists on acute migraine treatment met the eligibility criteria for this meta-analysis. The pooled analysis demonstrated that the CGRP receptor antagonist improved freedom from pain (OR=2.066, 95% confidence interval [CI] 1.766–2.418, I2=0%), absence of bothersome symptoms (OR=1.606, 95% CI=1.408–1.830, I2=0%), pain relief (OR=1.791, 95% CI=1.598–2.008, I2=0%), and freedom from nausea (OR=1.361, 95% CI=1.196–1.548, I2=0%), significantly more than the placebo. Conclusions: CGRP receptor antagonists are effective for acute migraine treatment and are expected to be used clinically as emerging therapeutic agents.

Download Full-text

Current status of calcitonin gene-related peptide-based therapies in migraine: a scoping review

International Journal of Basic & Clinical Pharmacology ◽

10.18203/2319-2003.ijbcp20220043 ◽

2022 ◽

Author(s):

Marya Ahsan ◽

Ayaz Khurram Mallick

Keyword(s):

Clinical Trials ◽

Monoclonal Antibodies ◽

Small Molecule ◽

Significant Proportion ◽

Calcitonin Gene Related Peptide ◽

Phase Iii ◽

Current Status ◽

Cgrp Receptor ◽

Related Peptide ◽

Calcitonin Gene

A significant proportion of patients exhibit sub-optimal response to the standard treatment of acute migraine such as triptans and NSAIDs. Even the conventional preventive therapies (e.g. beta-blockers) indicated for patients with frequent migraine attacks have varying responses. Moreover, evidence from animal studies elucidated the role of calcitonin gene-related peptide (CGRP) in the pathophysiology of migraine. Currently two classes are drug, the small molecule CGRP receptor antagonist or the ‘gepants’ (Ubrogepant, Rimegepant, Atogepant, Zavegepant) and CGRP monoclonal antibodies (Erenumab, Galcanezumab, Fremanezumab, Eptinezumab) have been found efficacious and safe in various clinical trials for the treatment and prevention of migraine. While the small molecule CGRP receptor antagonists are given orally, the monoclonal antibodies are injectable drugs. Ubrogepant and Rimegepant are the second-generation gepants approved for treatment of migraine. Zavegepant is a third generation gepant which has proven efficacy for acute treatment of migraine in a phase III trial. Atogepant has been approved for prevention of migraine. Rimegepant has also proven to be efficacious for preventing migraine attacks but has not yet been approved for this indication. Erenumab is the only monoclonal antibody which neutralizes the CGRP receptor. The latter three monoclonal antibodies target the CGRP peptide. The monoclonal antibodies have been approved for the prevention of migraine as a subcutaneously or intravenous infusion (Eptinezumab) given once a month or quarterly. Both the classes of drugs were well-tolerated in the clinical trials. Nausea was the most common adverse effect with gepants while injection-site pain was commonly reported with the antibodies.

Download Full-text

The synthesis and SAR of calcitonin gene-related peptide (CGRP) receptor antagonists derived from tyrosine surrogates. Part 1

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2012.05.074 ◽

2012 ◽

Vol 22 (14) ◽

pp. 4723-4727 ◽

Cited By ~ 11

Author(s):

Xiaojun Han ◽

Rita L. Civiello ◽

Charles M. Conway ◽

Deborah A. Cook ◽

Carl D. Davis ◽

...

Keyword(s):

Calcitonin Gene Related Peptide ◽

Cgrp Receptor ◽

Receptor Antagonists ◽

Related Peptide ◽

Calcitonin Gene ◽

Cgrp Receptor Antagonists

Download Full-text

A Short on Ubrogepant

Journal of Pharmaceutical Research International ◽

10.9734/jpri/2021/v33i56a33888 ◽

2021 ◽

pp. 79-81

Author(s):

S. Padmaja ◽

J. Mohan

Keyword(s):

Receptor Antagonist ◽

Research Process ◽

Calcitonin Gene Related Peptide ◽

Review Article ◽

Acute Migraine ◽

Cgrp Receptor ◽

Related Peptide ◽

Calcitonin Gene ◽

Acute Attacks ◽

Cgrp Receptor Antagonist

Migraine is a mysterious disorder characterized by pulsating head ache, which is actually characterized to one side and comes in attacks which will be lasting for about 3-48 hours and can be associated with nausea,vomiting,sensitivity to sound,flashes of light,vertigoand diarrhoea [1]. Most of the drugs which are in current use for actue migraine like triptans, treats the disorder symptomatically. A novel group of drugs has been in research for the migraine which treats the disorder pathologically. Calcitonin gene – related peptide (CGRP) has a major role in the pathophysiology of the disorder and hence CGRP receptor antagonist, known as Gepants are in the research process [2]. Gepants are being studied for the efficacy of treating acute migraine [2]. This article will be a review article about the drug – Ubrogepant, which is approved for treatment of migraine with acute attacks in adults [3].

Download Full-text

Rimegepant: first novel oral calcitonin gene-related peptide inhibitor for migraine

International Journal of Basic & Clinical Pharmacology ◽

10.18203/2319-2003.ijbcp20201768 ◽

2020 ◽

Vol 9 (5) ◽

pp. 829

Author(s):

Saravana Kumar Ramasubbu ◽

Senkadhirdasan Dakshinamurthy ◽

Sarika Palepu ◽

Arkapal Bandyopadhyay ◽

Sathish Kumar Rajendran

Keyword(s):

Area Under The Curve ◽

Cardiovascular Effects ◽

Calcitonin Gene Related Peptide ◽

Causative Role ◽

Acute Migraine ◽

Related Peptide ◽

Calcitonin Gene ◽

Effective Option ◽

Inflammatory Drugs ◽

Cgrp Antagonist

Migraine is a neurological condition characterized by intense, debilitating headaches. Symptoms may include nausea, vomiting, numbness or tingling, sensitivity to light and sound. There are multitude of drugs available to treat migraine like triptans, non-steroidal anti-inflammatory drugs, ergots and opioids. But these drugs are associated with adverse effects especially triptans causing cardiovascular effects limiting its use. During last decade, calcitonin gene-related peptide (CGRP) has emerged as a possible mechanism for management of migraine. CGRP has been shown to release during episode of migraine attack and it may play a causative role in induction of migraine. Rimegepant is a novel CGRP antagonist has been approved by FDA for treatment of acute migraine. Rimegepant is a first oral CGRP antagonist compared to other gepants. The oral bioavailability of Rimegepant is 64% and high fat meal can decrease the Cmax, Tmax and area under the curve. This drug is mainly metabolized by CYP3A4 and to lesser extent by CYP2C9. Most common adverse reactions associated with this drug were nausea and urinary tract infection. Clinical trials for Rimegepant have been positive, and results suggest that the drug may be a new safe and effective option for treatment of acute migraine.

Download Full-text

Quinine analogs as non-peptide calcitonin gene-related peptide (CGRP) receptor antagonists

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/s0960-894x(97)10046-4 ◽

1997 ◽

Vol 7 (20) ◽

pp. 2673-2676 ◽

Cited By ~ 15

Author(s):

Robert A. Daines ◽

Kelvin K.C. Sham ◽

Jack J. Taggart ◽

William D. Kingsbury ◽

James Chan ◽

...

Keyword(s):

Calcitonin Gene Related Peptide ◽

Cgrp Receptor ◽

Receptor Antagonists ◽

Related Peptide ◽

Calcitonin Gene ◽

Cgrp Receptor Antagonists

Download Full-text

Ubrogepant: First Approval

Drugs ◽

10.1007/s40265-020-01264-5 ◽

2020 ◽

Vol 80 (3) ◽

pp. 323-328 ◽

Cited By ~ 7

Author(s):

Lesley J. Scott

Keyword(s):

Small Molecule ◽

Acute Treatment ◽

Calcitonin Gene Related Peptide ◽

Migraine Aura ◽

Related Peptide ◽

Global Approval ◽

Calcitonin Gene ◽

The Usa ◽

Cgrp Antagonist

Abstract Ubrogepant (Ubrelvy™) is an orally administered, small molecule, highly-selective, calcitonin gene-related peptide (CGRP) antagonist that was developed by Allergan under license to Merck & Co. as an acute treatment for migraine. In December 2019, ubrogepant received its first global approval in the USA for the acute treatment of migraine (± aura) in adults. This article summarizes the milestones in the development of ubrogepant leading to its first global approval for the acute treatment of migraine (± aura) in adults.

Download Full-text