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

• Published in: ACS medicinal chemistry letters Vol. 5; no. 5; pp. 474 - 479
• Main Authors: Bhattacharya, Samit K, Andrews, Kim, Beveridge, Ramsay, Cameron, Kimberly O, Chen, Chiliu, Dunn, Matthew, Fernando, Dilinie, Gao, Hua, Hepworth, David, Jackson, V. Margaret, Khot, Vishal, Kong, Jimmy, Kosa, Rachel E, Lapham, Kimberly, Loria, Paula M, Londregan, Allyn T, McClure, Kim F, Orr, Suvi T. M, Patel, Jigna, Rose, Colin, Saenz, James, Stock, Ingrid A, Storer, Gregory, VanVolkenburg, Maria, Vrieze, Derek, Wang, Guoqiang, Xiao, Jun, Zhang, Yingxin
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 08.05.2014; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Letter; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; ghrelin receptor antagonist; ghrelin receptor inverse agonist; PF-5190457; Ghrelin; diabetes; GSK1614343; INSULIN-SECRETION; INFUSION; IDENTIFICATION; P-GLYCOPROTEIN; INHIBITION; PHARMACOKINETICS; GLUCOSE; ANTAGONISTS; EFFICIENCY
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/ml400473x

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.