Novel Growth Hormone Secretagogues Show Enhanced Potency and Oral Bioavailability
Background
Growth hormone secretagogues (GHS) are compounds that stimulate the release of growth hormone from the pituitary gland, holding potential for conditions like growth hormone deficiency or muscle wasting. Previous research comparing ipamorelin and NN703 suggested that adding a polar group to the C-terminus of NN703 could enhance potency, but the optimal structural modifications for this were unclear. This study aimed to design and synthesize novel GHS with improved potency by exploring conformational restriction in their C-terminal region.
Results
The synthesized compounds, particularly those incorporating 4-hydroxypiperidino substituents, demonstrated high in vitro activity with EC50 values in the low nanomolar range. These compounds also exhibited favorable pharmacokinetic properties, including an impressive 40% oral bioavailability. > The most promising compound, when tested in a swine model, significantly elevated growth hormone levels, achieving a Cmax of over 40 ng/mL in the blood. This indicates a substantial increase in systemic growth hormone compared to baseline, suggesting potent in vivo efficacy and a significant improvement over previous GHS candidates.
Why It Matters
This research successfully identified novel growth hormone secretagogues with significantly improved potency and, crucially, excellent oral bioavailability. The development of orally active GHS is a major step forward, as it offers a more convenient and patient-friendly administration route compared to injectables. This could pave the way for new therapeutic options for conditions requiring growth hormone stimulation, such as sarcopenia, cachexia, or growth hormone deficiency. Future work would involve further preclinical optimization and eventually human clinical trials (e.g., Phase I) to confirm safety and efficacy.