A potent, orally bioavailable benzazepinone growth hormone secretagogue.
The identification of L-739,943 (8b), a potent, orally bioavailable benzolactam growth hormone secretagogue, is obtained from zwitterionic L-692,429 through modification of its amino acid side chain and replacement of the acidic 2'-tetrazole with the neutral and potency enhancing 2'-(N-methylaminocarbonylamino)methyl substituent. L-739,943 is orally active for the release of growth hormone in beagle dogs at doses as low as 0.5 mg/kg. Oral bioavailability in dogs of 8b is 24% at a dose of 2 mg/kg with a mean drug Cmax of 145 +/- 46 ng/mL. L-739,943 represents a significant breakthrough in terms of both potency and oral bioavailability as compared to the prototype benzolactam L-692,429.
DeVita
R J
RJ
Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065-0900, USA.
Bochis
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Frontier
A J
AJ
Kotliar
A
A
Fisher
M H
MH
Schoen
W R
WR
Wyvratt
M J
MJ
Cheng
K
K
Chan
W W
WW
Butler
B
B
Jacks
T M
TM
Hickey
G J
GJ
Schleim
K D
KD
Leung
K
K
Chen
Z
Z
Chiu
S L
SL
Feeney
W P
WP
Cunningham
P K
PK
Smith
R G
RG
D000284:Administration, Oral; D000818:Animals; D001552:Benzazepines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D002478:Cells, Cultured; D004285:Dogs; D005260:Female; D013006:Growth Hormone / Q000378:metabolism*; D008297:Male; D008782:Methylurea Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D010902:Pituitary Gland / Q000166:cytology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000494:pharmacology
D001552:Benzazepines; D008782:Methylurea Compounds; D013777:Tetrazoles; C081455:L 692429; D013006:Growth Hormone; C112108:L 739943