A New Oral Growth Hormone Pill 100 Times More Potent Than MK-677 Increased Growth in Young Rats

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.

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.

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.

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.

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.