A nonpeptidyl secretagogue for growth hormone of the structure 3-amino-3-methyl-N-(2,3,4,5-tetrahydro-2-oxo-1-([2'-(1H-tetrazol-5 -yl) (1,1'-biphenyl)-4-yl]methyl)-1H-1-benzazepin-3(R)-yl)-butanamid e (L-692,429) has been identified. L-692,429 synergizes with the natural growth hormone secretagogue growth hormone-releasing hormone and acts through an alternative signal transduction pathway. The mechanism of action of L-692,429 and studies with peptidyl and nonpeptidyl antagonists suggest that this molecule is a mimic of the growth hormone-releasing hexapeptide His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GHRP-6). L-692,429 is an example of a nonpeptidyl specific secretagogue for growth hormone.
We report the synthesis of a series of phosphinic acid dipeptide analogues, NH2CH(R1)PO(OH)CH2CH(R2)CO2H, related to DAla-DAla. The best of these compounds are potent, essentially irreversible inhibitors of DAla-DAla ligase, and their preferred stereochemistry was shown by chiral synthesis of (1(S)-aminoethyl)(2(R)-carboxy-1-n-propyl)phosphinic acid, 12b, and by X-ray crystallography of its derivative benzyl [1(S)-[(benzyloxycarbonyl)-amino]ethyl](2(R)-carbomethoxy-1-propyl) phosphinate, 13, to correspond to the stereochemical configuration of DAla-DAla at both centers. A mechanism for the inhibition of DAla-DAla ligase by these compounds is proposed to involve an ATP-dependent formation of phosphorylated inhibitor within the enzyme's active site. The antibacterial activities of these compounds are modest although their spectra include both Gram-positive and Gram-negative susceptible organisms. The best antibacterial activity was shown by (1(S)-aminoethyl) [2-carboxy-2(R)-(methylthio)-1-ethyl]phosphinic acid, 3e, whose MIC's range from 4-128 micrograms/mL on nine of a panel of 11 bacterial organisms. Combination of one of the more active phosphinic acids 12b with the alanine racemase inhibitor fluoro-D-alanine enhances the antibacterial spectrum of the latter on several strains of bacteria and inhibits fluoro-D-alanine's self-reversal, which normally occurs at concentrations several fold higher than its MIC level. This inhibition of fluoro-D-alanine self-reversal is consistent with an involvement of DAla-DAla ligase inhibition in the antibacterial activity of these compounds.
L-692,585 is a 2-hydroxypropyl derivative of L-692,429, both novel non-peptidyl growth hormone (GH) secretagogues. The effects of single and repeated intravenous administration of L-692,585 on serum or plasma GH and other hormones in beagles were evaluated. In a balanced 8-dog dose-ranging study, compared to the saline control with a mean (+/- S.E.M.) after-dose serum GH peak of 6.1 +/- 1.3 ng/ml, L-692,585 significantly increased (P < 0.05) peak GH concentrations 4.3-fold (32.5 +/- 7.0 ng/ml) at a dose of 0.005 mg/kg, 7-fold (49.4 +/- 10.6 ng/ml) at a dose of 0.02 mg/kg, and 21-fold (134.3 +/- 29.0 ng/ml) at a dose of 0.10 mg/kg. Total GH release, expressed as area under the curve, showed a similar dose-dependent increase. Peak GH levels were recorded at 5 or 15 min after dosing with the levels returning to near baseline by 90 min. Serum cortisol levels were increased above saline control levels in a dose-dependent manner; however, the increases were modest compared to the GH increases. Based on peak responses and total GH release, L-692,585 was 10- to 20-fold and 2- to 2.5-fold more potent than L-692,429 and the growth hormone releasing peptide, GHRP-6, respectively. When L-692,585 was administered once daily for 14 consecutive days at 0, 0.01 or 0.10 mg/kg to each of 6 dogs, peak plasma GH levels and total GH release on days 1, 8 and 15 significantly increased in a dose-dependent manner, and no desensitization was evident.(ABSTRACT TRUNCATED AT 250 WORDS)
L-692,429, a benzolactam derivative, stimulated GH release from rat primary pituitary cells in a dose-dependent manner. The concentration of L-692,429 required for half-maximal stimulation were 59.6 +/- 7.3 nM. Under the same conditions, GHRP-6 and GRF had EC50 values of 10.3 +/- 1.9 nM and 0.47 +/- 0.09 nM, respectively. L-692,428, the enantiomer of L-692,429, was inactive at a concentration as high as 2 microM. Like GHRP-6, L-692,429 had no effect on intracellular cAMP level; however, it synergized with GRF to further increase not only the accumulation of cAMP but also the release of GH. The magnitude of GH release stimulated by maximal concentrations of L-692,429 and GHRP-6 was comparable. Interestingly, when presented together in maximal concentrations, L-692,429 and GHRP-6 did not cause additional GH release when compared with either secretagogue alone. The L-692,429-stimulated GH release was completely inhibited by 20 nM somatostatin. To our knowledge, L-692,429 is the first non-peptidyl GH secretagogue which has a direct effect on the release of growth hormone from rat primary pituitary cells. Its effect is most likely mediated through a mechanism which is similar to that of GHRP-6.
The 3-substituted benzazepinone, L-692,429 (compound 1), is the prototype compound of a novel class of compounds that stimulate release of growth hormone (GH). The molecule evolved from efforts to identify a non-peptide mimic of the growth hormone-releasing hexapeptide, GHRP-6. Compound 1 is prepared by sequential attachment of dimethyl-beta-alanine and 2'-biphenylyltetrazole side chains to a chiral 3-aminobenzolactam nucleus. Comparison of the biological activity of 1 with the corresponding six- and eight-membered lactam analogs shows the seven-membered benzazepinone skeleton to be preferred. Molecular modeling of the structurally diverse GH secretagogues, L-692,429 and GHRP-6, was performed.
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