pyrimidinones and Migraine-Disorders

Transient-receptor-potential melastatin 8 (TRPM8), the predominant mammalian cold-temperature thermosensor, is a nonselective cation channel expressed in a subpopulation of sensory neurons in the peripheral nervous system, including nerve circuitry implicated in migraine pathogenesis: the trigeminal and pterygopalatine ganglia. Genomewide association studies have identified an association between TRPM8 and reduced risk of migraine. This disclosure focuses on medicinal-chemistry efforts to improve the druglike properties of initial leads, particularly removal of CYP3A4-induction liability and improvement of pharmacokinetic properties. A novel series of biarylmethanamide TRPM8 antagonists was developed, and a subset of leads were evaluated in preclinical toxicology studies to identify a clinical candidate with an acceptable preclinical safety profile leading to clinical candidate AMG 333, a potent and highly selective antagonist of TRPM8 that was evaluated in human clinical trials.

Topics: Animals; Anticonvulsants; Calcium Channel Agonists; Drug Discovery; Humans; Male; Microsomes, Liver; Migraine Disorders; Models, Molecular; Molecular Structure; Niacin; Pyrimidinones; Rats; Rats, Sprague-Dawley; Seizures; TRPM Cation Channels

Migraine headache is a neurological disorder affecting millions worldwide. However, little is known about the mechanisms contributing to migraine. Recent genome-wide association studies have found single nucleotide polymorphisms in the gene encoding transient receptor potential channel M8. Transient receptor potential channel M8 is generally known as a cold receptor but it has been implicated in pain signaling and may play a role in migraine pain.. In order to investigate whether transient receptor potential channel M8 may contribute to the pain of migraine, the transient receptor potential channel M8 activator icilin was applied to the dura mater using a rat behavioral model of headache. Cutaneous allodynia was measured for 5 hours using Von Frey filaments.. Dural application of icilin produced cutaneous facial and hind paw allodynia that was attenuated by systemic pretreatment with the transient receptor potential channel M8-selective antagonist AMG1161 (10 mg/kg p.o.). Further, the anti-migraine agent sumatriptan (0.6 mg/kg s.c.) or the non-selective NOS inhibitor L-NAME (20 mg/kg i.p.) also attenuated allodynia when given as a pretreatment.. These data indicate that transient receptor potential channel M8 activation in the meninges produces behaviors in rats that are consistent with migraine and that are sensitive to pharmacological mechanisms known to have efficacy for migraine in humans. The findings suggest that activation of meningeal transient receptor potential channel M8 may contribute to the pain of migraine.

Topics: Animals; Disease Models, Animal; Hyperalgesia; Male; Migraine Disorders; Pyrimidinones; Rats; Rats, Sprague-Dawley; TRPM Cation Channels

Since the brain 5HT2 receptors might be implicated in migraine pathogenesis, we have used positron emission tomography and 18F-fluorosetoperone, a 5HT2 specific radioligand, to investigate in vivo the cortical 5HT2 receptors in migraine subjects. Nine migraineurs who had either migraine with and without aura (n = 5) or only migraine without aura (n = 4) were studied between attacks. Twelve unmedicated healthy subjects of similar mean age were used as controls. Brain radioactivity was measured after 18F-setoperone IV injection for 90 min. A decrease of the regional specific distribution volumes (SDV) of the ligand was observed both in migraineurs and in controls. The age adjusted group means of SDV did not differ between patients and controls for the whole and for the right or left frontal, temporal, parietal and occipital cortex. These results suggest that cortical 5HT2 receptors may be unaltered between attacks in migraine sufferers.

Topics: Adult; Case-Control Studies; Cerebral Cortex; Fluorine Radioisotopes; Humans; Middle Aged; Migraine Disorders; Pyrimidinones; Radioligand Assay; Receptors, Serotonin; Statistics as Topic; Tomography, Emission-Computed