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.