Discovery of the Potent and Selective MC4R Antagonist PF-07258669 for the Potential Treatment of Appetite Loss

The melanocortin-4 receptor (MC4R) is a centrally expressed,
class
A GPCR that plays a key role in the regulation of appetite and food
intake. Deficiencies in MC4R signaling result in hyperphagia and increased
body mass in humans. Antagonism of MC4R signaling has the potential
to mitigate decreased appetite and body weight loss in the setting
of anorexia or cachexia due to underlying disease. Herein, we report
on the identification of a series of orally bioavailable, small-molecule
MC4R antagonists using a focused hit identification effort and the
optimization of these antagonists to provide clinical candidate 23. Introduction of a spirocyclic conformational constraint
allowed for simultaneous optimization of MC4R potency and ADME attributes
while avoiding the production of hERG active metabolites observed
in early series leads. Compound 23 is a potent and selective
MC4R antagonist with robust efficacy in an aged rat model of cachexia
and has progressed into clinical trials.