Novel Oxindole Derivative Potently Stimulates Growth Hormone, Shows Oral Activity
Background
Growth hormone (GH) plays a crucial role in growth, metabolism, and body composition. Conditions like growth hormone deficiency can lead to impaired growth in children and various metabolic issues in adults. While GH replacement therapy exists, there's a continuous search for orally active compounds, known as growth hormone secretagogues (GHS), that can stimulate the body's own GH production. This study aimed to synthesize and evaluate novel oxindole derivatives to identify potent, orally bioavailable GHS candidates with improved pharmacological profiles.
Results
SM-130686 (37S) demonstrated exceptionally potent GH-releasing activity in cultured rat pituitary cells, with an EC50 of 3.0 nM, while its other enantiomer, 37R, showed significantly reduced activity. Pharmacokinetic analysis revealed a good oral bioavailability of 28% in rats following a 10 mg/kg oral dose. Crucially, SM-130686 (37S) exhibited excellent in vivo activity, leading to a significant and measurable weight gain in rats after just 4 days of oral administration at 10 mg/kg twice a day. Furthermore, SM-130686 (37S) displayed high affinity for the human GHS-R, effectively displacing (35)S-MK-677 with an IC50 value of 1.2 ± 0.2 nM, indicating it acts as a potent agonist at this receptor.
Why It Matters
The identification of SM-130686 (37S) represents a significant step forward, as it is an orally active, highly potent growth hormone secretagogue with a favorable pharmacokinetic profile in rats. Its ability to induce significant weight gain in vivo suggests potential therapeutic applications for conditions characterized by growth hormone deficiency, muscle wasting, or cachexia. This compound could serve as a promising lead for the development of new, convenient oral treatments for patients needing GH stimulation. Future research will likely focus on more extensive preclinical toxicology, long-term efficacy studies, and eventually, human clinical trials to confirm its safety and effectiveness.