title: Growth hormone response in man to L-692,429, a novel nonpeptide mimic of growth hormone-releasing peptide-6.
abstract: L-692,429, a substituted benzolactam, is a novel nonpeptide mimic of the GH secretagogue, GH-releasing peptide-6. The safety and GH secretory activity of L-692,429 (0.001-1.0 mg/kg, i.v.) were investigated in 24 healthy nonobese young (18-26 yr old) male volunteers who demonstrated a GH response of 7 micrograms/L or more after 1 microgram/kg, i.v. GH-releasing hormone [GH-releasing hormone-(1-29)NH2]. L-692,429 was administered as a 15-min iv infusion in an incremental dose, double blind, placebo-controlled, alternating panel fashion to 3 panels of 8 subjects each. Dose-dependent GH secretion was observed with a threshold dose of 0.05 mg/kg (4 of 6 subjects responded with peak GH > 7 micrograms/L), and 0.2 mg/kg produced a response in all 14 subjects tested (mean +/- SE peak GH, 41.0 +/- 6.3 micrograms/L). The maximum dose of 1.0 mg/kg L-692,429 resulted in a pronounced GH response (peak GH, 82.5 +/- 14.9 micrograms/L; n = 8). The GH peak was seen 30-45 min after initiation of the infusion. Small transient increases in cortical and PRL were observed (increases in cortical averaged 182.1 +/- 33.1 nmol/L and peak PRL was 21 +/- 2.6 micrograms/L after 1.0 mg/kg L-692,429, respectively), whereas no significant changes occurred in LH, FSH, TSH, insulin, or glucose concentrations. Plasma pharmacokinetic analysis revealed dose-related increases in plasma concentrations 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 distribution 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-692,429 or more, but no other clinical or laboratory adverse experiences appeared related to drug treatment. L-692,429, synthesized as a specific nonpeptide mimic of GH-releasing peptide-6, is thus a well tolerated, highly effective, and selective GH secretagogue in man.
authors.affiliation: Merck Research Laboratories, Rahway, New Jersey 07065.
authors.forename: B J
authors.initials: BJ
authors.lastname: Gertz
authors.forename: J S
authors.initials: JS
authors.lastname: Barrett
authors.forename: R
authors.initials: R
authors.lastname: Eisenhandler
authors.forename: D A
authors.initials: DA
authors.lastname: Krupa
authors.forename: J M
authors.initials: JM
authors.lastname: Wittreich
authors.forename: J R
authors.initials: JR
authors.lastname: Seibold
authors.forename: S H
authors.initials: SH
authors.lastname: Schneider
mesh_terms: D000293:Adolescent; D000328:Adult; D001552:Benzazepines / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D004311:Double-Blind Method; D013006:Growth Hormone / Q000097:blood*; D013007:Growth Hormone-Releasing Hormone / Q000494:pharmacology; D006728:Hormones / Q000097:blood; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology*; D009994:Osmolar Concentration; D010919:Placebos; D011388:Prolactin / Q000097:blood; D013777:Tetrazoles / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*
chemical_list: D001552:Benzazepines; D006728:Hormones; D009842:Oligopeptides; D010919:Placebos; D013777:Tetrazoles; C081455:L 692429; C041048:growth hormone releasing hexapeptide; D011388:Prolactin; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone; D006854:Hydrocortisone