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

British Journal of Pharmacology
Jimmy KongV Margaret Jackson

Abstract

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. 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. 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 compa...Continue Reading

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Citations

Apr 6, 2017·International Journal of Molecular Sciences·Rareş-Petru MoldovanPeter Brust
Mar 16, 2019·Endocrinology·Bharath K ManiJeffrey M Zigman
Aug 29, 2017·SLAS Discovery·Mariko Yoneyama-HirozaneJunichi Sakamoto
Feb 15, 2020·Alcoholism, Clinical and Experimental Research·George Kunos
Sep 12, 2019·Current Diabetes Reports·Martha A Schalla, Andreas Stengel

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