Low molecular weight peptidomimetic growth hormone secretagogues

Abstract

The present invention comprises growth hormone releasing peptides/peptidomimetics (GHRP) capable of causing release of growth hormone from the pituitary. Compositions containing the GHRP's of this invention are used to promote growth in mammals either alone or in combination with other growth promoting compounds, especially IGF-1. In a method of this invention GHRP's in combination with IGF-1 are used to treat Type II diabetes. An exemplary compound of this invention is provided below.

Description

[0001] The invention relates to synthetic peptidomimetics having growth hormone releasing activity in mammals. The peptidomimetics of this invention are used to stimulate the release of endogenous growth hormone (GH) in mammals needing elevation of serum growth hormone levels.[0002] GH secretion is known to be inhibited by the hypothalamic hormone somatostatin (SS) and stimulated by GH-releasing hormone (GHRH) in all mammalian species studied including humans. In man, GH is released from the anterior pituitary somatotrophs in pulsatile secretory bursts occurring about 4-8 times in each 24 hour period (Devesa, J., et al., Trends Endocrinol Metab. 3:175-183 [1992] and Mason, W. T., et al., Acta Paediatr Suppl 388:84-92 [1993]). This episodic release pattern seems to be optimal for inducing the physiological effects of GH since many target tissues appear to be more sensitive to the frequency than the total amount of GH arriving at the target tissue (Robinson and Clark Growth Hormone: B...

AI Technical Summary

Benefits of technology

0131] FIG. 24. Basal blood glucose levels obtained weekly in lean (small squares) and obese Type II Zucker Diabetic Fatty (ZDF) male rats treated for 3 weeks subcutaneously with excipient (controls, solid circles), recombinant human growth hormone (rhGH, open squares, 500 .mu.g / d), recombinant human insulin-like growth factor-1 (rhIGF-1, open circles, 758 .mu.g / d), (inip) bbFK-NH.sub.2 given by injection (100 .mu.g / d; open triangles), or the combination of rhGH and rhIGF-1 (solid squares), or the combination of rhIGF-1 and (inip) bbFK-NH.sub.2 (solid triangles). When given alone, or in combination with rhIGF-1, (inip) bbFK-NH.sub.2 had lesser effect on blood glucose (diabetogenic effect) than rhGH at doses with similar somatogenic effects (FIG. 22). Means and standard errors are shown.

0132] FIG. 25. Blood glucose concentrations following an intravenous insulin challenge (insulin tolerance test) in lean control male rats (open bar), obese Type II Zucker Diabetic Fatty (ZDF) rats treated subcutaneously with excipient (solid bar), recombinant human growth hormone (rhGH, light left-right ascending hatching, 500 .mu.g / d), recombinant human insulin-like growth factor-1 (rhIGF-1, light shaded bar, 758 .mu.g / d), (inip) bbFK-NH.sub.2 given by injection (100 .mu.g / d; light left-right descending hatching), or the combination of rhGH and rhIGF-1 (heavy left-right ascending hatching), or the combination of rhIGF-1 and (inip) bbFK-NH.sub.2 (heavy left-right descending hatching). When given alone, or in combination with rhIGF-1, (inip) bbFK-NH.sub.2 had a greatly reduced effect on insulin sensitivity (diabetogenic effect) than rhGH at doses with similar somatogenic effects (FIG. 22). Means and standard errors are shown.

Problems solved by technology

These peptides, however, generally lack specificity for GH release.

A number of structurally diverse nonpeptidyl GH secretagogues (e.g. Talipexole and Clonidine) are reported to stimulate GH release in vitro and in vivo, but these compounds are believed to mediate their effect through cholinergic, adrenergic, dopaminergic or serotonergic pathways and thus also lack GH releasing specificity.

A number of these compounds (e.g., "GHRP-6" and L-692,429) are reported to be safe and effective in promoting endogenous GH release in humans, however, there remain problems with oral availability and specificity.

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