Fragment-Based Discovery of an Oral Calcitonin Gene-Related Peptide Receptor Antagonist for the Treatment of Migraine

Calcitonin gene-related peptide (CGRP) receptor antagonists
have
demonstrated clinical efficacy in the treatment of migraine. In this
study, we performed surface plasmon resonance-based fragment screening
to identify various site binders and estimated their binding modes
based on surface plasmon resonance and nuclear magnetic resonance
studies using mutated CGRP receptors. Two fragment hits were merged
and optimized to create compound 15, which showed good
oral bioavailability in rats, attractive preclinical properties overall,
and robust activity in a primate model of CGRP-induced facial blood
flow.

降钙素基因相关肽（Calcitonin gene-related peptide, CGRP）受体拮抗剂在偏头痛的治疗中已展现出明确的临床疗效。本研究采用基于表面等离子体共振（surface plasmon resonance, SPR）的片段筛选方法，筛选得到多种位点结合剂，并借助搭载突变型CGRP受体的表面等离子体共振与核磁共振（nuclear magnetic resonance, NMR）实验，对各结合剂的结合模式进行了评估。将两个片段命中物进行合并与优化，得到化合物15；该化合物在大鼠体内展现出良好的口服生物利用度，整体具备优异的临床前特性，且在CGRP诱导的面部血流量灵长类动物模型中表现出强劲的生物学活性。