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

Abstract

BACKGROUND AND PURPOSEGhrelin 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 APPROACHRadioligand 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 RESULTSPF-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 K d 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 K i in recombinant overexpressing cells. The effect of PF-05190457 on rodent islets was comparable with glibenclamide, but glucosedependent and additive with the insulin secretagogue glucagon-like peptide-1. CONCLUSIONS AND IMPLICATIONSTogether, 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. Abbreviations

Pharmacokinetics and pharmacodynamics of PF‐05190457: The first oral ghrelin receptor inverse agonist to be profiled in healthy subjects

“…The ghrelin ED 50 was determined in this study to be lower than the literature-reported 5 pmol kg -1 min -1 , and the ghrelin infusion rate of 1 pmol kg -1 min -1 was found to better approximate the ED 50 . As expected, PF-05190457 dosedependently inhibited the ghrelin-induced GH with a maximum inhibition observed at a 100 mg PF-05190457 BID, which achieved maximum free concentrations of approximately 18-fold the human K i [57,69].…”

“…Ex vivo, ghrelin decreases glucose-induced insulin release in rodent islets and perfused pancreas [22,24,25,71,72]. PF-05190457 increased intracellular calcium within rat dispersed islets and increased insulin secretion from human islets ex vivo in a glucose-dependent manner [57,69]. However, PF-05190457 did not act as an insulin secretagogue in healthy volunteers as postprandial insulin was not modulated.…”

Ghrelin regulation of glucose metabolism

“…Pfizer recently developed a GHSR1a receptor antagonist, PF-05190457, that is currently in clinical evaluation for the treatment of T2D. This drug shows beneficial effect on glucose-dependent insulin secretion in vitro , and increases insulin secretion in isolated human islet [ 137 , 138 ]. Interestingly, PF-05190457 was stopped after the phase I clinical trials but nor for safety reasons [ 139 ] and it remains in clinical evaluation for the treatment of insomnia [ 140 ].…”

Interactions Between Alcohol and the Endocannabinoid System

“…Interestingly, vagal afferent nerve firing is decreased by signals that increase alcohol intake, such as ghrelin (Date et al, 2002), whereas it is increased by blockade of peripheral ghrelin receptors (Kong et al, 2016) or by cholecystokinin (Date et al, 2002; Schwartz et al, 1997), which also reduces alcohol intake (Geary et al, 2004). The apparent reciprocal relationship between vagal afferent nerve firing and alcohol preference is compatible with the increased incidence of alcoholism following Roux‐en‐Y gastric bypass surgery, which disrupts gastric innervation (Hajnal et al, 2012), and results in loss of ghrelin regulation of the firing of VTA dopaminergic neurons (Sirohi et al, 2017).…”