PRT-064040: A nasal spray of novel, potent, and selective calcitonin gene-related peptide receptor antagonist for migraine

Calcitonin gene-related peptide (CGRP), a neuropeptide, has been implicated in autoimmune diseases, endometriosis, tumors, and primary headaches, including migraine. The development of a novel, fast-acting CGRP receptor antagonist administered via nasal spray could address current clinical demands. PRT-064040, a novel, potent, and selective CGRP receptor antagonist, was discovered and developed by Sichuan Purity Pharmaceutical Co, Ltd. Its pharmacological characteristics were investigated through a series of experimental studies. In vitro assays, including radioligand binding and cAMP accumulation functional assays, demonstrated that PRT-064040 possesses high affinity for the human CGRP receptor (Ki = 26.67 ± 6.27 pM) and effectively inhibited human αCGRP-induced cAMP production (IC50 = 22.29 pM). The compound exhibited high selectivity within the calcitonin family member, with an IC50 of 5.38 nM for amylin receptor 1 and no inhibitory activity on other closely related receptors at concentrations up to 10 μM. In vivo efficacy was evaluated using a human αCGRP-induced dermal blood flow model in cynomolgus monkeys, in which PRT-064040 dose-dependently attenuated αCGRP-mediated dermal vasodilation. Following nasal administration in rats, brain penetration of PRT-064040 was minimal. Pharmacokinetic profiling in cynomolgus monkeys revealed rapid absorption (time to maximum concentration (Tmax) = 10-15 minutes) postnasal delivery. Collectively, these findings indicate that PRT-064040 functions as a competitive antagonist with high affinity, potency, and selectivity for the human CGRP receptor. Moreover, a potent, concentration-dependent relationship was observed between plasma levels of PRT-064040 and inhibition of αCGRP-mediated physiological effects. SIGNIFICANCE STATEMENT: This study demonstrates that PRT-064040 is a competitive antagonist exhibiting high affinity, potency, and selectivity for the human calcitonin gene-related peptide receptor. Its rapid absorption at low doses may not only facilitate a fast-onset action but also suggest a potential for reduced adverse events in clinical practice.