Design, Biological Characterization, and Discovery of Capromorelin Derivatives as Oral Growth Hormone Secretagogue Receptor Type 1a Agonist for the Treatment of Growth Hormone Deficiency
Year: 2025
Type: article
Abstract: 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 4b (hGHSR-1a EC 50 = 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 4b 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 4b 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 4b, which demonstrates a promising pharmacological profile for clinical translation as a growth hormone replacement therapy.
Source: Journal of Medicinal Chemistry
Authors: Hang Xu, Meng Liu, Xiangyu Jia, Sheng Zhao, Yuanfeng Xia, Biao Lu, Fanglong Yang, Siqin Wang, Lei Jin
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4408535183