Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Therapeutic Discovery, Amgen Research, Amgen Inc., 1120 Veterans Blvd., South San Francisco, California 94080, United States.
J Med Chem. 2021 Mar 25;64(6):3427-3438. doi: 10.1021/acs.jmedchem.0c01396. Epub 2021 Mar 15.
Inhibition of the pituitary adenylate cyclase 1 receptor (PAC1R) is a novel mechanism that could be used for abortive treatment of acute migraine. Our research began with comparative analysis of known PAC1R ligand scaffolds, PACAP38 and Maxadilan, which resulted in the selection of des(24-42) Maxadilan, , as a starting point. C-terminal modifications of improved the peptide metabolic stability and . SAR investigations identified synergistic combinations of amino acid replacements that significantly increased the PAC1R inhibitory activity of the analogs to the pM IC range. Our modifications further enabled deletion of up to six residues without impacting potency, thus improving peptide ligand binding efficiency. Analogs and exhibited robust efficacy in the rat Maxadilan-induced increase in blood flow (MIIBF) pharmacodynamic model at 0.3 mg/kg subcutaneous dosing. The first cocrystal structure of a PAC1R antagonist peptide () with PAC1R extracellular domain is reported.
抑制垂体腺苷酸环化酶 1 受体（PAC1R）是一种新的机制，可以用于急性偏头痛的失败治疗。我们的研究始于对已知 PAC1R 配体支架 PACAP38 和 Maxadilan 的比较分析，这导致选择了去（24-42）Maxadilan 作为起点。C 端修饰提高了肽的代谢稳定性和 。SAR 研究确定了氨基酸替换的协同组合，显著提高了类似物对 PAC1R 的抑制活性，达到 pM IC 范围。我们的修饰进一步使多达六个残基的缺失成为可能，而不影响效力，从而提高了肽配体的结合效率。类似物 和 在大鼠 Maxadilan 诱导的血流量增加（MIIBF）药效学模型中，在 0.3 mg/kg 皮下给药剂量下表现出强大的 疗效。报告了第一个 PAC1R 拮抗剂肽（）与 PAC1R 细胞外结构域的共晶结构。
