Calcitonin Gene-Related Peptide Receptor Antagonists for the Treatment of Migraine

Theresa M. Williams1; Christopher S. Burgey1; Christopher A. Salvatore2    1 Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
2 Department of Pain Research, Merck Research Laboratories, West Point, PA 19486, USA

Introduction

Migraine headache is a disabling condition with characteristic symptoms that can last for several days. The earliest written descriptions of migraine date from ancient Sumeria circa 3000–4000 BC [1]. Primitive treatment included trepanation, in which a hole was drilled in the skull in an attempt to alleviate head pain.

Caffeine was probably the first pharmacological agent to treat migraine, and it is likely that the availability and prevalence of coffee in 17th-century England helped to popularize this remedy. Two hundred years later, ergot extracts were discovered to be useful in treating some headaches [2]. More widespread use followed when pure, crystalline ergotamine tartrate was obtained in 1918, and in 1925 the successful treatment of migraine with subcutaneous ergotamine (ET) was achieved [3]. Hydrogenation of the 9,10 double bond produced dihydroergotamine (DHT), which was better tolerated than ET and effective in treating migraine. Both ET and DHT bind with high affinity to multiple serotonin, noradrenaline and dopamine receptors. Since rare but potentially serious adverse cardiac events have been reported, the use of ET and DHT is contraindicated in patients with cardiovascular disease.

The discovery of subtype-selective serotonin agonists known as triptans significantly improved treatment options. First introduced in 1993, this class of drugs revolutionized migraine therapy and is now considered the “gold standard”. Triptans bind and activate 5-HT1B and 5-HT1D receptors to promote vasoconstriction of cranial blood vessels, and to block inflammatory peptide release in sensory neurons [4]. Unlike ET and DHT, triptans are orally bioavailable, convenient to dose and generally well tolerated. These drugs are safe when used appropriately but, because they cause vasoconstriction, triptans are also contraindicated in patients with cardiovascular disease.

After the successful introduction of the triptans, evidence began to accumulate linking calcitonin gene-related peptide (CGRP) to migraine pathophysiology. CGRP had been identified as a vasoactive neuropeptide largely expressed in sensory neurons [5]. It was observed that plasma levels of CGRP were elevated during migraine, and that successful treatment with a triptan returned it to basal levels [6, 7]. This observation, along with other evidence, suggested that CGRP receptor antagonists might be useful antimigraine drugs. Because CGRP receptor antagonists are not direct vasoconstrictors, it was suggested that they would not have the cardiovascular liabilities associated with triptans, and thus could possess a therapeutic advantage. Clinical proof of concept was obtained with the potent CGRP receptor antagonist BIBN4096BS (olcegepant) (1) [8]. Following iv administration, BIBN4096BS proved efficacious in treating acute migraine headache in human clinical trials. A practical goal was to identify a CGRP receptor antagonist that was orally bioavailable and thus convenient for patients to take. This was the focus of the medicinal chemistry effort that led to the discovery of MK-0974 (telcagepant) (2), an oral CGRP receptor antagonist [9, 10].

This review seeks to summarize key aspects of research in the discovery and characterization of CGRP receptor antagonists for therapeutic application to the treatment of migraine.

Migraine and a role for CGRP

Epidemiology and Clinical Manifestations of Migraine

Migraine is a common and disabling neurological disorder estimated to afflict 11% of the global adult population [11]. Prevalence ranges from 6 to 9% among men and 15 to 17% among women [12]. After gender, the second biggest factor associated with migraine is age. Migraine prevalence increases with age, peaking in the middle years (40–50 years of age) and decreasing thereafter [13]. The severity and high prevalence of migraine headache is estimated to have a societal cost of $16.6 billion in the United States [14]. A variety of indirect costs, including absenteeism and reduced productivity at work, account for a large portion of this cost. Migraine is generally agreed to be under-diagnosed. A population-based survey identified individuals with severe headache that met the criteria for migraine, but about 50% of these migraineurs had not been diagnosed by a physician [15]. Therefore there is a significant opportunity for improvement in the diagnosis and management of migraine [14, 15].

Migraine can be separated into five phases: the prodrome, aura, headache, resolution and postdrome phases [12]. The most common prodrome (premonitory) symptoms reported by approximately 60% of migraineurs are fatigue, mood changes and gastrointestinal symptoms [16, 17]. The large proportion of migraineurs experiencing prodrome symptoms underscores the potential for preventing the headache phase with early pharmacological intervention. An acute migraine attack does not always include an aura phase. When present, aura typically occurs just before or simultaneously with the headache. Aura is characterized by one or more transient, neurologic visual, sensory, motor, aphasic or basilar symptoms, typically lasting less than 60 min [12, 18]. In adults, untreated migraine attacks without aura have typically unilateral head pain, last between 4 and 72 h and are accompanied by one or more of the following: nausea, vomiting, sensitivity to sound and sensitivity to light [19].

CGRP and Migraine

CGRP is a 37 amino acid neuropeptide belonging to the calcitonin family of peptides which includes calcitonin, adrenomedullin and amylin. CGRP exists in two forms, α- and β-CGRP, which differ from each other by three amino acids. α-CGRP (3) is produced by tissue specific alternative mRNA splicing of the calcitonin gene [20], whereas β-CGRP is encoded by a discrete gene which does not produce calcitonin [21, 22]. Of the two forms, it is considered that α-CGRP is the more abundant and it is found in discrete areas of the central and peripheral nervous system [23]. Although there are proposed differences in the receptor-mediated effects of α- and β-CGRP, throughout this review it is the effects of α-CGRP (3) which will be discussed.

CGRP is widely distributed in the peripheral and central nervous system [24] and exhibits a wide range of biological effects on tissues, the most pronounced being vasodilation [25]. Cerebral blood vessels are densely innervated by CGRP-expressing trigeminal nerve endings [26] and the vasoactive effects of CGRP have been demonstrated in a variety of blood vessels, including those of the cerebral vasculature [27]. The above observations are aligned with the early theories proposed over 60 years ago by Wolff [28] that migraine is related to dilation of the extracerebral vasculature. It has been demonstrated that stimulation of the trigeminal ganglia in both cats and humans results in the elevation of CGRP in the cranial circulation [29] and analogously, that CGRP levels are increased in the cranial circulation during severe migraine attacks [30, 31]. Intravenous administration of CGRP to migraineurs induced a delayed migrainous headache in some patients [32], and successful treatment of migraine headache with sumatriptan resulted in the normalization of CGRP levels [33].

The prevailing consensus view is that migraine is a neurological disorder, where the primary site of dysfunction resides in the brain [34]. This is supported by the following observations: (1) positron emission tomography showed evidence of brainstem activation during a migrainous attack [35]; (2) intravenous administration of the potent CGRP receptor antagonist BIBN4096BS reduced spontaneous...