title: 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: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors.affiliation: Cardiovascular and Metabolic Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA, 01239, USA.
authors.forename: J
authors.initials: J
authors.lastname: Kong
authors.affiliation: Cardiovascular and Metabolic Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA, 01239, USA.
authors.forename: J
authors.initials: J
authors.lastname: Chuddy
authors.affiliation: Cardiovascular and Metabolic Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA, 01239, USA.
authors.forename: I A
authors.initials: IA
authors.lastname: Stock
authors.affiliation: Cardiovascular and Metabolic Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA, 01239, USA.
authors.forename: P M
authors.initials: PM
authors.lastname: Loria
authors.affiliation: Cardiovascular and Metabolic Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA, 01239, USA.
authors.forename: S V
authors.initials: SV
authors.lastname: Straub
authors.affiliation: Cardiovascular and Metabolic Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA, 01239, USA.
authors.forename: C
authors.initials: C
authors.lastname: Vage
authors.affiliation: Cardiovascular and Metabolic Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA, 01239, USA.
authors.forename: K O
authors.initials: KO
authors.lastname: Cameron
authors.affiliation: Cardiovascular and Metabolic Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA, 01239, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Bhattacharya
authors.affiliation: Cardiovascular and Metabolic Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA, 01239, USA.
authors.forename: K
authors.initials: K
authors.lastname: Lapham
authors.affiliation: Cardiovascular and Metabolic Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA, 01239, USA.
authors.forename: K F
authors.initials: KF
authors.lastname: McClure
authors.affiliation: Cardiovascular and Metabolic Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA, 01239, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Cardiovascular and Metabolic Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA, 01239, USA.
authors.forename: V M
authors.initials: VM
authors.lastname: Jackson
mesh_terms: D000818:Animals; D001384:Azetidines / Q000737:chemistry / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D054314:Drug Inverse Agonism; D005947:Glucose / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D054440:Receptors, Ghrelin / Q000037:antagonists & inhibitors*; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014630:Vagus Nerve / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology
chemical_list: D001384:Azetidines; D007328:Insulin; C000606714:PF-5190457; D054440:Receptors, Ghrelin; D013141:Spiro Compounds; D005947:Glucose; D002118:Calcium