Design, Biological Characterization, and Discovery of Capromorelin Derivatives as Oral Growth Hormone Secretagogue Receptor Type 1a Agonist for the Treatment of Growth Hormone Deficiency

Recombinant human growth hormone (rhGH) is a well-established treatment for children with growth deficiencies worldwide. However, its requirement for subcutaneous administration limits convenience compared to that of oral therapies. Starting from capromorelin, we designed, synthesized, and characterized a novel orally active GHSR-1a agonist, compound <b>4b</b> (hGHSR-1a EC₅₀ = 0.49 nM), which effectively stimulates endogenous GH release in rats at oral doses as low as 0.1 mg/kg─100-fold more potent than ibutamoren (10 mg/kg). Notably, 10 day oral administration of <b>4b</b> increased body weight and length in 4-week-old rats. To date, comprehensive preclinical studies on oral agents for short stature remain limited, and existing GHSR-1a agonists lack approval for this indication. Compound <b>4b</b> exhibited superior pharmacokinetic exposure in dogs (oral bioavailability: 43.6%; half-life: 1.2 h) relative to other species. This study details the optimization of <b>4b</b>, which demonstrates a promising pharmacological profile for clinical translation as a growth hormone replacement therapy.