GROWTH-HORMONE RESPONSE IN MAN TO L-692,429, A NOVEL NONPEPTIDE MIMICOF GROWTH HORMONE-RELEASING PEPTIDE-6

L-692,429, a substituted benzolactam, is a novel nonpeptide mimic of t he GH secretagogue, GH-releasing peptide-G. The safety and GH secretor y activity of L-692,429 (0.001-1.0 mg/kg, iv) were investigated in 24 healthy nonobese young (18-26 yr old) male volunteers who demonstrated a GH response of 7 mu g/L or more after 1 mu g/kg, iv, GH-releasing h ormone [GH-releasing hormone-(1-29)NH2]. L-692,429 was administered as a 15-min iv infusion in an incremental dose, double blind, placebo-co ntrolled, alternating panel fashion to 3 panels of 8 subjects each. Do se-dependent GH secretion was observed with a threshold dose 0.05 mg/k g (4 of 6 subjects responded with peak GH >7 mu g/L), and 0.2 mg/kg pr oduced a response in all 14 subjects tested (mean +/- SE peak GH, 41.0 +/- 6.3 mu g/L). The maximum dose of 1.0 mg/kg L-692,429 resulted in a pronounced GH response (peak GH, 82.5 +/- 14.9 mu g/L; n = 8). The G H peak was seen 30-45 min after initiation of the infusion. Small tran sient increases in cortisol and PRL were observed (increases in cortis ol averaged 182.1 +/- 33.1 nmol/L and peak PRL was 21 +/- 2.6 mu g/L a fter 1.0 mg/kg L-692,429, respectively), whereas no significant change s occurred in LH, FSH, TSH, insulin, or glucose concentrations. Plasma pharmacokinetic analysis revealed dose-related increases in plasma co ncentrations of L-692,429 and a half-life of 3.8 +/- 0.2 (+/-SE) h, a plasma clearance of 214 +/- 67 mL/min, and a steady state volume of di stribution of 14.2 +/- 4.8 L. Facial flushing or a warm sensation were reported in 4 subjects, primarily at dose levels of 0.2 mg/kg L-692,4 29 or more, but no other clinical or laboratory adverse experiences ap peared related to drug treatment. L-692,429, synthesized as a specific nonpeptide mimic of GH-releasing peptide-G, is thus a well tolerated, highly effective, and selective GH secretagogue in man.