A capromorelin-derived oral compound stimulates growth hormone release at 100-fold lower doses than ibutamoren and increased body weight and length in young rats after 10 days of treatment.
100× more potent than MK-677Compound 4b stimulated GH release in rats at 0.1 mg/kg orally, compared to 10 mg/kg needed for ibutamoren
What the researchers found
Starting from capromorelin, researchers designed compound 4b, a novel oral ghrelin receptor (GHSR-1a) agonist with an EC50 of 0.49 nM — making it 100-fold more potent than ibutamoren (MK-677) at stimulating endogenous growth hormone release in rats. At oral doses as low as 0.1 mg/kg, compound 4b effectively triggered GH secretion. In young rats, 10 days of oral treatment increased both body weight and body length. In dogs, the compound showed 43.6% oral bioavailability with a 1.2-hour half-life.
Why it matters
Children with growth hormone deficiency currently require daily injections of recombinant growth hormone — a significant burden for young patients and their families. An oral pill that stimulates the body's own GH production could transform treatment. While MK-677 (ibutamoren) has been the most well-known oral GH secretagogue, compound 4b is 100 times more potent and showed actual growth effects in young animals, making it a more promising clinical candidate.
How the study worked
The researchers performed structure-activity relationship (SAR) optimization starting from capromorelin to design a series of derivatives. Compound 4b was evaluated for receptor binding potency (EC50 at GHSR-1a), oral pharmacokinetics in multiple species (rats and dogs), and in vivo GH release in rats. A 10-day oral dosing study in 4-week-old rats measured effects on body weight and length as indicators of growth stimulation.
What this study cannot tell us
This is a preclinical study — no human data were collected. The 10-day growth study in rats is short, and longer-term efficacy, safety, and effects on IGF-1 levels and bone growth plates are unknown. The 1.2-hour half-life in dogs may require multiple daily doses. Potential side effects associated with GH secretagogues (appetite stimulation, insulin resistance, water retention) were not fully characterized.
How to read the evidence
This is a preclinical medicinal chemistry study demonstrating compound optimization and efficacy in rats and dogs. It represents early drug development with no human data yet available.
When this study was published
Published in 2025, this is very recent work pushing the state of the art in oral GH secretagogue development. The compound has not yet entered clinical trials.
The bigger picture
Growth hormone secretagogues have been studied for decades, but none have been approved for treating short stature in children. MK-677 remains the most discussed compound in this class but was never approved. This new compound's dramatically improved potency and demonstrated growth effects in young animals represent a significant advance. If it reaches clinical trials, it could address a major unmet need — replacing painful daily injections with a simple pill for children who need growth hormone therapy.
Questions still open
- Will the growth-promoting effects seen in 10-day rat studies translate to meaningful height gains in children with GH deficiency?
- What are the long-term safety implications of chronically stimulating GH release via the ghrelin receptor, particularly regarding insulin resistance and cancer risk?
- How does the short half-life (1.2 hours in dogs) affect dosing convenience — would extended-release formulations be needed?
Common questions
How is this different from MK-677 (ibutamoren)?
Why can't children with growth hormone deficiency just take a pill right now?
Read the original research
Design, Biological Characterization, and Discovery of Capromorelin Derivatives as Oral Growth Hormone Secretagogue Receptor Type 1a Agonist for the Treatment of Growth Hormone Deficiency.
Journal of medicinal chemistry, 68(6), 6766-6788
Citation
Xu, Hang; Liu, Meng; Jia, Xiangyu; Zhao, Sheng; Xia, Yuanfeng; Lu, Biao; Yang, Fanglong; Wang, Siqin; Jin, Lei. (2025). Design, Biological Characterization, and Discovery of Capromorelin Derivatives as Oral Growth Hormone Secretagogue Receptor Type 1a Agonist for the Treatment of Growth Hormone Deficiency.. Journal of medicinal chemistry, 68(6), 6766-6788. https://doi.org/10.1021/acs.jmedchem.5c00217