Discovery of PF-5190457, a Potent, Selective, and Orally Bioavailable Ghrelin Receptor Inverse Agonist Clinical Candidate

  • ACS Med Chem Lett. 2014 Feb 24;5(5):474-9. doi: 10.1021/ml400473x.
Samit K Bhattacharya  1 ,  Kim Andrews  1 ,  Ramsay Beveridge  1 ,  Kimberly O Cameron  1 ,  Chiliu Chen  1 ,  Matthew Dunn  1 ,  Dilinie Fernando  1 ,  Hua Gao  1 ,  David Hepworth  1 ,  V Margaret Jackson  1 ,  Vishal Khot  1 ,  Jimmy Kong  1 ,  Rachel E Kosa  1 ,  Kimberly Lapham  1 ,  Paula M Loria  1 ,  Allyn T Londregan  1 ,  Kim F McClure  1 ,  Suvi T M Orr  1 ,  Jigna Patel  1 ,  Colin Rose  1 ,  James Saenz  1 ,  Ingrid A Stock  1 ,  Gregory Storer  1 ,  Maria VanVolkenburg  1 ,  Derek Vrieze  1 ,  Guoqiang Wang  1 ,  Jun Xiao  1 ,  Yingxin Zhang  1
Affiliations
  • 1. 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.
PMID: 24900864 DOI: 10.1021/ml400473x
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.

Keywords
Ghrelin; PF-5190457; diabetes; ghrelin receptor antagonist; ghrelin receptor inverse agonist.
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