期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 5, 期 5, 页码 474-479出版社
AMER CHEMICAL SOC
DOI: 10.1021/ml400473x
关键词
Ghrelin; ghrelin receptor inverse agonist; ghrelin receptor antagonist; diabetes; PF-5190457
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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