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

Area of Science:

• Pharmacology
• Medicinal Chemistry
• Endocrinology

Background:

• The melanocortin-4 receptor (MC4R), a class A GPCR, is crucial for regulating appetite and body mass.
• MC4R signaling deficiencies lead to hyperphagia and obesity in humans.
• MC4R antagonism offers a therapeutic strategy for counteracting appetite loss and weight reduction in diseases like anorexia and cachexia.

Purpose of the Study:

• To identify and optimize orally bioavailable small-molecule antagonists of the melanocortin-4 receptor (MC4R).
• To develop a clinical candidate for potential therapeutic applications in conditions characterized by appetite loss and weight loss.

Main Methods:

• Focused hit identification and lead optimization of MC4R antagonists.
• Introduction of spirocyclic conformational constraints to enhance potency and ADME properties.
• Evaluation of compound 23 in an aged rat model of cachexia.

Main Results:

• Identification of a series of orally bioavailable MC4R antagonists.
• Optimization led to clinical candidate 23, featuring spirocyclic constraints for improved potency and ADME profiles.
• Compound 23 demonstrated potent and selective MC4R antagonism and efficacy in a cachexia rat model.
• Avoidance of hERG active metabolites was achieved through structural modifications.

Conclusions:

• Compound 23 is a potent and selective MC4R antagonist with demonstrated efficacy in a preclinical model of cachexia.
• The developed spirocyclic constraint strategy successfully optimized MC4R antagonists for therapeutic development.
• Compound 23 has advanced to clinical trials, indicating its therapeutic potential for cachexia and related conditions.