title: Discovery of PF-5190457, a Potent, Selective, and Orally Bioavailable Ghrelin Receptor Inverse Agonist Clinical Candidate.
abstract: The identification of potent, highly selective orally bioavailable ghrelin receptor inverse agonists from a spiro-azetidino-piperidine series is described. Examples from this series have promising in vivo pharmacokinetics and increase glucose-stimulated insulin secretion in human whole and dispersed islets. A physicochemistry-based strategy to increase lipophilic efficiency for ghrelin receptor potency and retain low clearance and satisfactory permeability while reducing off-target pharmacology led to the discovery of 16h. Compound 16h has a superior balance of ghrelin receptor pharmacology and off-target selectivity. On the basis of its promising pharmacological and safety profile, 16h was advanced to human clinical trials.
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Samit K
authors.initials: SK
authors.lastname: Bhattacharya
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Kim
authors.initials: K
authors.lastname: Andrews
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Ramsay
authors.initials: R
authors.lastname: Beveridge
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Kimberly O
authors.initials: KO
authors.lastname: Cameron
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Chiliu
authors.initials: C
authors.lastname: Chen
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Matthew
authors.initials: M
authors.lastname: Dunn
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Dilinie
authors.initials: D
authors.lastname: Fernando
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Hua
authors.initials: H
authors.lastname: Gao
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: David
authors.initials: D
authors.lastname: Hepworth
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: V Margaret
authors.initials: VM
authors.lastname: Jackson
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Vishal
authors.initials: V
authors.lastname: Khot
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Jimmy
authors.initials: J
authors.lastname: Kong
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Kosa
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Lapham
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Paula M
authors.initials: PM
authors.lastname: Loria
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Allyn T
authors.initials: AT
authors.lastname: Londregan
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Kim F
authors.initials: KF
authors.lastname: McClure
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Suvi T M
authors.initials: ST
authors.lastname: Orr
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Jigna
authors.initials: J
authors.lastname: Patel
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Colin
authors.initials: C
authors.lastname: Rose
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: James
authors.initials: J
authors.lastname: Saenz
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Ingrid A
authors.initials: IA
authors.lastname: Stock
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Gregory
authors.initials: G
authors.lastname: Storer
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Maria
authors.initials: M
authors.lastname: VanVolkenburg
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Derek
authors.initials: D
authors.lastname: Vrieze
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Wang
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Jun
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Yingxin
authors.initials: Y
authors.lastname: Zhang
keywords: Ghrelin; PF-5190457; diabetes; ghrelin receptor antagonist; ghrelin receptor inverse agonist