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Discovery of PF-5190457, a Potent, Selective, and Orally Bioavailable Ghrelin Receptor Inverse Agonist Clinical Candidate. 2014
Samit K Bhattacharya, and
Kim Andrews, and
Ramsay Beveridge, and
Kimberly O Cameron, and
Chiliu Chen, and
Matthew Dunn, and
Dilinie Fernando, and
Hua Gao, and
David Hepworth, and
V Margaret Jackson, and
Vishal Khot, and
Jimmy Kong, and
Rachel E Kosa, and
Kimberly Lapham, and
Paula M Loria, and
Allyn T Londregan, and
Kim F McClure, and
Suvi T M Orr, and
Jigna Patel, and
Colin Rose, and
James Saenz, and
Ingrid A Stock, and
Gregory Storer, and
Maria VanVolkenburg, and
Derek Vrieze, and
Guoqiang Wang, and
Jun Xiao, and
Yingxin Zhang
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.
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.
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