首个临床候选药物PF-05190457的药理学特性：一种具有反向激动作用的选择性胃饥饿素受体竞争性拮抗剂，可增加离体迷走神经传入放电和葡萄糖依赖性胰岛素分泌。
Pharmacological characterization of the first in class clinical candidate PF-05190457: a selective ghrelin receptor competitive antagonist with inverse agonism that increases vagal afferent firing and glucose-dependent insulin secretion ex vivo.
作者信息
Kong J, Chuddy J, Stock I A, Loria P M, Straub S V, Vage C, Cameron K O, Bhattacharya S K, Lapham K, McClure K F, Zhang Y, Jackson V M
机构信息
Cardiovascular and Metabolic Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA, 01239, USA.
出版信息
Br J Pharmacol. 2016 May;173(9):1452-64. doi: 10.1111/bph.13439. Epub 2016 Mar 17.
BACKGROUND AND PURPOSE
Ghrelin increases growth hormone secretion, gastric acid secretion, gastric motility and hunger but decreases glucose-dependent insulin secretion and insulin sensitivity in humans. Antagonizing the ghrelin receptor has potential as a therapeutic approach in the treatment of obesity and type 2 diabetes. Therefore, the aim was to pharmacologically characterize the novel small-molecule antagonist PF-05190457 and assess translational pharmacology ex vivo.
EXPERIMENTAL APPROACH
Radioligand binding in filter and scintillation proximity assay formats were used to evaluate affinity, and europium-labelled GTP to assess functional activity. Rat vagal afferent firing and calcium imaging in dispersed islets were used as native tissues underlying food intake and insulin secretion respectively.
KEY RESULTS
PF-05190457 was a potent and selective inverse agonist on constitutively active ghrelin receptors and acted as a competitive antagonist of ghrelin action, with a human Kd of 3 nM requiring 4 h to achieve equilibrium. Potency of PF-05190457 was similar across different species. PF-05190457 increased intracellular calcium within dispersed islets and increased vagal afferent firing in a concentration-dependent manner with similar potency but was threefold less potent as compared with the in vitro Ki in recombinant overexpressing cells. The effect of PF-05190457 on rodent islets was comparable with glibenclamide, but glucose-dependent and additive with the insulin secretagogue glucagon-like peptide-1.
CONCLUSIONS AND IMPLICATIONS
Together, these data provide the pharmacological in vitro and ex vivo characterization of the first ghrelin receptor inverse agonist, which has advanced into clinical trials to evaluate the therapeutic potential of blocking ghrelin receptors in obesity and type 2 diabetes.
背景与目的
胃饥饿素可增加生长激素分泌、胃酸分泌、胃动力并引发饥饿感，但会降低人体葡萄糖依赖性胰岛素分泌及胰岛素敏感性。拮抗胃饥饿素受体在肥胖症和2型糖尿病的治疗中具有潜在的治疗价值。因此，本研究旨在对新型小分子拮抗剂PF - 05190457进行药理学特性分析，并评估其体外转化药理学特性。
实验方法
采用滤膜结合法和闪烁邻近分析法进行放射性配体结合实验，以评估亲和力，并用铕标记的GTP评估功能活性。分别将大鼠迷走神经传入放电和分散胰岛中的钙成像作为食物摄入和胰岛素分泌的天然组织模型。
关键结果
PF - 05190457是组成型激活的胃饥饿素受体的强效选择性反向激动剂，可作为胃饥饿素作用的竞争性拮抗剂，其对人的解离常数（Kd）为3 nM，达到平衡需要4小时。PF - 05190457在不同物种中的效力相似。PF - 05190457可使分散胰岛内的细胞内钙增加，并以浓度依赖性方式增加迷走神经传入放电，效力相似，但与重组过表达细胞中的体外抑制常数（Ki）相比，效力低三倍。PF - 05190457对啮齿动物胰岛的作用与格列本脲相当，但具有葡萄糖依赖性，且与胰岛素促分泌剂胰高血糖素样肽 - 1具有相加作用。
结论与意义
这些数据共同提供了首个胃饥饿素受体反向激动剂的体外和体外药理学特性，该激动剂已进入临床试验，以评估阻断胃饥饿素受体在肥胖症和2型糖尿病中的治疗潜力。
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