Design and Biological Activities of L-163,191 (MK-0677): A Potent, Orally Active Growth Hormone Secretagogue

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 92; no. 15; pp. 7001 - 7005
• Main Authors: Patchett, A. A., Nargund, R. P., Tata, J. R., M.-H. Chen, Barakat, K. J., Johnston, D. B. R., Cheng, K., W. W.-S. CHan, Butler, B., Hickey, G., Jacks, T., Schleim, K., S.-S. Pong, L.-Y. P. Chaung, Chen, H. Y., Frazier, E., Leung, K. H., S.-H. L. Chiu, Smith, Roy G.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 18.07.1995; National Acad Sciences; National Academy of Sciences
• Subjects: Administration, Oral; Aldosterone - blood; Amino Acid Sequence; Aminoisobutyric acids; Animals; Benzazepines - pharmacology; Bioavailability; Calcium; Cells, Cultured; Chemistry; Dogs; Drug Design; Drug Synergism; Endocrinology; Growth Hormone - metabolism; Growth hormones; Hormones; Indoles - administration & dosage; Indoles - pharmacology; Injections, Intravenous; Lead; Luteinization; Luteinizing Hormone - blood; Male; Medical research; Molecular Sequence Data; Oligopeptides; Pituitary Gland - drug effects; Prolactin - blood; Rats; Receptors; Salts; Spiro Compounds - administration & dosage; Spiro Compounds - pharmacology; Structure-Activity Relationship; Tetrazoles - pharmacology; Thyroxine - blood
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.92.15.7001

A potent, orally active growth hormone (GH) secretagogue L-163,191 belonging to a recently synthesized structural class has been characterized. L-163,191 releases GH from rat pituitary cells in culture with EC50= 1.3 ± 0.09 nM and is mechanistically indistinguishable from the GH-releasing peptide GHRP-6 and the prototypical nonpeptide GH secretagogue L-692,429 but clearly distinguishable from the natural GH secretagogue, GH-releasing hormone. L-163,191 elevates GH in dogs after oral doses as low as 0.125 mg/kg and was shown to be specific in its release of GH without significant effect on plasma levels of aldosterone, luteinizing hormone, thyroxine, and prolactin after oral administration of 1 mg/kg. Only modest increases in cortisol were observed. Based on these properties, L-163,191 has been selected for clinical studies.