Design and biological activities of L-163,191 (MK-0677): a potent, orally active growth hormone secretagogue.
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.
Patchett
A A
AA
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065-0900, USA.
Nargund
R P
RP
Tata
J R
JR
Chen
M H
MH
Barakat
K J
KJ
Johnston
D B
DB
Cheng
K
K
Chan
W W
WW
Butler
B
B
Hickey
G
G
D000284:Administration, Oral; D000450:Aldosterone / Q000097:blood; D000595:Amino Acid Sequence; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D002478:Cells, Cultured; D004285:Dogs; D015195:Drug Design; D004357:Drug Synergism; D013006:Growth Hormone / Q000378:metabolism*; D007211:Indoles / Q000008:administration & dosage* / Q000494:pharmacology; D007275:Injections, Intravenous; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D008969:Molecular Sequence Data; D009842:Oligopeptides; D010902:Pituitary Gland / Q000187:drug effects*; D011388:Prolactin / Q000097:blood; D051381:Rats; D013141:Spiro Compounds / Q000008:administration & dosage* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000494:pharmacology; D013974:Thyroxine / Q000097:blood
D001552:Benzazepines; D007211:Indoles; D009842:Oligopeptides; D013141:Spiro Compounds; D013777:Tetrazoles; C081455:L 692429; D000450:Aldosterone; C041048:growth hormone releasing hexapeptide; D011388:Prolactin; D007986:Luteinizing Hormone; D013006:Growth Hormone; D013974:Thyroxine; C094817:ibutamoren mesylate