2. Academic Validation
  3. Discovery of PF-5190457, a Potent, Selective, and Orally Bioavailable Ghrelin Receptor Inverse Agonist Clinical Candidate

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

Affiliation

  • 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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