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. 1995 Jul 18;92(15):7001–7005. doi: 10.1073/pnas.92.15.7001

Design and biological activities of L-163,191 (MK-0677): a potent, orally active growth hormone secretagogue.

A A Patchett 1, R P Nargund 1, J R Tata 1, M H Chen 1, K J Barakat 1, D B Johnston 1, K Cheng 1, W W Chan 1, B Butler 1, G Hickey 1, et al.
PMCID: PMC41459  PMID: 7624358

Abstract

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.

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Selected References

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  1. Aloi J. A., Gertz B. J., Hartman M. L., Huhn W. C., Pezzoli S. S., Wittreich J. M., Krupa D. A., Thorner M. O. Neuroendocrine responses to a novel growth hormone secretagogue, L-692,429, in healthy older subjects. J Clin Endocrinol Metab. 1994 Oct;79(4):943–949. doi: 10.1210/jcem.79.4.7962302. [DOI] [PubMed] [Google Scholar]
  2. Andrews P. R., Lloyd E. J. Molecular conformation and biological activity of central nervous system active drugs. Med Res Rev. 1982 Oct-Dec;2(4):355–393. doi: 10.1002/med.2610020404. [DOI] [PubMed] [Google Scholar]
  3. Bowers C. Y. GH releasing peptides--structure and kinetics. J Pediatr Endocrinol. 1993 Jan-Mar;6(1):21–31. doi: 10.1515/jpem.1993.6.1.21. [DOI] [PubMed] [Google Scholar]
  4. Bowers C. Y., Momany F. A., Reynolds G. A., Hong A. On the in vitro and in vivo activity of a new synthetic hexapeptide that acts on the pituitary to specifically release growth hormone. Endocrinology. 1984 May;114(5):1537–1545. doi: 10.1210/endo-114-5-1537. [DOI] [PubMed] [Google Scholar]
  5. Bowers C. Y. On a peptidomimetic growth hormone-releasing peptide. J Clin Endocrinol Metab. 1994 Oct;79(4):940–942. doi: 10.1210/jcem.79.4.7962301. [DOI] [PubMed] [Google Scholar]
  6. Bowers C. Y., Reynolds G. A., Durham D., Barrera C. M., Pezzoli S. S., Thorner M. O. Growth hormone (GH)-releasing peptide stimulates GH release in normal men and acts synergistically with GH-releasing hormone. J Clin Endocrinol Metab. 1990 Apr;70(4):975–982. doi: 10.1210/jcem-70-4-975. [DOI] [PubMed] [Google Scholar]
  7. Chambers M. S., Baker R., Billington D. C., Knight A. K., Middlemiss D. N., Wong E. H. Spiropiperidines as high-affinity, selective sigma ligands. J Med Chem. 1992 May 29;35(11):2033–2039. doi: 10.1021/jm00089a013. [DOI] [PubMed] [Google Scholar]
  8. Cheng K., Chan W. W., Barreto A., Jr, Convey E. M., Smith R. G. The synergistic effects of His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 on growth hormone (GH)-releasing factor-stimulated GH release and intracellular adenosine 3',5'-monophosphate accumulation in rat primary pituitary cell culture. Endocrinology. 1989 Jun;124(6):2791–2798. doi: 10.1210/endo-124-6-2791. [DOI] [PubMed] [Google Scholar]
  9. Cheng K., Chan W. W., Butler B., Barreto A., Jr, Smith R. G. Evidence for a role of protein kinase-C in His-D-Trp-Ala-Trp-D-Phe-Lys-NH2-induced growth hormone release from rat primary pituitary cells. Endocrinology. 1991 Dec;129(6):3337–3342. doi: 10.1210/endo-129-6-3337. [DOI] [PubMed] [Google Scholar]
  10. Cheng K., Chan W. W., Butler B., Wei L., Schoen W. R., Wyvratt M. J., Jr, Fisher M. H., Smith R. G. Stimulation of growth hormone release from rat primary pituitary cells by L-692,429, a novel non-peptidyl GH secretagogue. Endocrinology. 1993 Jun;132(6):2729–2731. doi: 10.1210/endo.132.6.8389289. [DOI] [PubMed] [Google Scholar]
  11. Dickson S. L., Leng G., Dyball R. E., Smith R. G. Central actions of peptide and non-peptide growth hormone secretagogues in the rat. Neuroendocrinology. 1995 Jan;61(1):36–43. doi: 10.1159/000126825. [DOI] [PubMed] [Google Scholar]
  12. Evans B. E., Bock M. G., Rittle K. E., DiPardo R. M., Whitter W. L., Veber D. F., Anderson P. S., Freidinger R. M. Design of potent, orally effective, nonpeptidal antagonists of the peptide hormone cholecystokinin. Proc Natl Acad Sci U S A. 1986 Jul;83(13):4918–4922. doi: 10.1073/pnas.83.13.4918. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Evans B. E., Leighton J. L., Rittle K. E., Gilbert K. F., Lundell G. F., Gould N. P., Hobbs D. W., DiPardo R. M., Veber D. F., Pettibone D. J. Orally active, nonpeptide oxytocin antagonists. J Med Chem. 1992 Oct 16;35(21):3919–3927. doi: 10.1021/jm00099a020. [DOI] [PubMed] [Google Scholar]
  14. Evans B. E., Rittle K. E., Bock M. G., DiPardo R. M., Freidinger R. M., Whitter W. L., Lundell G. F., Veber D. F., Anderson P. S., Chang R. S. Methods for drug discovery: development of potent, selective, orally effective cholecystokinin antagonists. J Med Chem. 1988 Dec;31(12):2235–2246. doi: 10.1021/jm00120a002. [DOI] [PubMed] [Google Scholar]
  15. Gertz B. J., Barrett J. S., Eisenhandler R., Krupa D. A., Wittreich J. M., Seibold J. R., Schneider S. H. Growth hormone response in man to L-692,429, a novel nonpeptide mimic of growth hormone-releasing peptide-6. J Clin Endocrinol Metab. 1993 Nov;77(5):1393–1397. doi: 10.1210/jcem.77.5.8077339. [DOI] [PubMed] [Google Scholar]
  16. Ghigo E., Arvat E., Gianotti L., Imbimbo B. P., Lenaerts V., Deghenghi R., Camanni F. Growth hormone-releasing activity of hexarelin, a new synthetic hexapeptide, after intravenous, subcutaneous, intranasal, and oral administration in man. J Clin Endocrinol Metab. 1994 Mar;78(3):693–698. doi: 10.1210/jcem.78.3.8126144. [DOI] [PubMed] [Google Scholar]
  17. Hartman M. L., Farello G., Pezzoli S. S., Thorner M. O. Oral administration of growth hormone (GH)-releasing peptide stimulates GH secretion in normal men. J Clin Endocrinol Metab. 1992 Jun;74(6):1378–1384. doi: 10.1210/jcem.74.6.1592884. [DOI] [PubMed] [Google Scholar]
  18. Hickey G., Jacks T., Judith F., Taylor J., Schoen W. R., Krupa D., Cunningham P., Clark J., Smith R. G. Efficacy and specificity of L-692,429, a novel nonpeptidyl growth hormone secretagogue, in beagles. Endocrinology. 1994 Feb;134(2):695–701. doi: 10.1210/endo.134.2.8299565. [DOI] [PubMed] [Google Scholar]
  19. Hintz R. L. Untoward events in patients treated with growth hormone in the USA. Horm Res. 1992;38 (Suppl 1):44–49. doi: 10.1159/000182569. [DOI] [PubMed] [Google Scholar]
  20. Laron Z., Frenkel J., Gil-Ad I., Klinger B., Lubin E., Wuthrich P., Boutignon F., Lengerts V., Deghenghi R. Growth hormone releasing activity by intranasal administration of a synthetic hexapeptide (hexarelin). Clin Endocrinol (Oxf) 1994 Oct;41(4):539–541. doi: 10.1111/j.1365-2265.1994.tb02589.x. [DOI] [PubMed] [Google Scholar]
  21. Momany F. A., Bowers C. Y., Reynolds G. A., Chang D., Hong A., Newlander K. Design, synthesis, and biological activity of peptides which release growth hormone in vitro. Endocrinology. 1981 Jan;108(1):31–39. doi: 10.1210/endo-108-1-31. [DOI] [PubMed] [Google Scholar]
  22. Momany F. A., Bowers C. Y., Reynolds G. A., Hong A., Newlander K. Conformational energy studies and in vitro and in vivo activity data on growth hormone-releasing peptides. Endocrinology. 1984 May;114(5):1531–1536. doi: 10.1210/endo-114-5-1531. [DOI] [PubMed] [Google Scholar]
  23. Neill J. D., Frawley L. S. Detection of hormone release from individual cells in mixed populations using a reverse hemolytic plaque assay. Endocrinology. 1983 Mar;112(3):1135–1137. doi: 10.1210/endo-112-3-1135. [DOI] [PubMed] [Google Scholar]
  24. Ong H. H., Profitt J. A., Fortunato J., Glamkowski E. J., Ellis D. B., Geyer H. M., Wilker J. C., Burghard H. Novel tetracyclic spiropiperidines. 3. 1-arylspiro[indoline-3,4'-piperidine]s as potential antidepressants. J Med Chem. 1983 Jul;26(7):981–986. doi: 10.1021/jm00361a009. [DOI] [PubMed] [Google Scholar]
  25. Smith R. G., Cheng K., Schoen W. R., Pong S. S., Hickey G., Jacks T., Butler B., Chan W. W., Chaung L. Y., Judith F. A nonpeptidyl growth hormone secretagogue. Science. 1993 Jun 11;260(5114):1640–1643. doi: 10.1126/science.8503009. [DOI] [PubMed] [Google Scholar]

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