Capromorelin: A Novel Oral Growth Hormone Secretagogue for Musculoskeletal Frailty

Growth Hormone Secretagogues (GHSs) are compounds that stimulate the release of Growth Hormone (GH), a crucial hormone involved in metabolism, growth, and tissue repair. These compounds hold significant therapeutic promise for conditions characterized by GH deficiency or muscle wasting, such as musculoskeletal frailty in elderly adults. However, the development of orally bioavailable GHSs with favorable pharmacokinetic properties has historically been a major challenge in drug discovery.

The study revealed that capromorelin exhibited high binding affinity for the human GHS-R1a receptor with a K(i) of just 7 nM, while its des-methyl analogue 5c showed a K(i) of 17 nM. Both compounds were highly potent in stimulating GH release from rat pituicytes, achieving an EC(50) of 3 nM for both. In an anesthesized rat model, both capromorelin and 5c significantly increased plasma GH levels, demonstrating potent in vivo activity with ED(50) values of less than 0.05 mg/kg intravenously. Capromorelin demonstrated superior pharmacokinetic properties, including enhanced intestinal absorption in rodent models and high oral bioavailabilities of 65% in rats and 44% in dogs, confirming its effectiveness as an orally active GHS in canine models.