title: A potent, orally bioavailable benzazepinone growth hormone secretagogue.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065-0900, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: DeVita
authors.forename: R
authors.initials: R
authors.lastname: Bochis
authors.forename: A J
authors.initials: AJ
authors.lastname: Frontier
authors.forename: A
authors.initials: A
authors.lastname: Kotliar
authors.forename: M H
authors.initials: MH
authors.lastname: Fisher
authors.forename: W R
authors.initials: WR
authors.lastname: Schoen
authors.forename: M J
authors.initials: MJ
authors.lastname: Wyvratt
authors.forename: K
authors.initials: K
authors.lastname: Cheng
authors.forename: W W
authors.initials: WW
authors.lastname: Chan
authors.forename: B
authors.initials: B
authors.lastname: Butler
authors.forename: T M
authors.initials: TM
authors.lastname: Jacks
authors.forename: G J
authors.initials: GJ
authors.lastname: Hickey
authors.forename: K D
authors.initials: KD
authors.lastname: Schleim
authors.forename: K
authors.initials: K
authors.lastname: Leung
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.forename: S L
authors.initials: SL
authors.lastname: Chiu
authors.forename: W P
authors.initials: WP
authors.lastname: Feeney
authors.forename: P K
authors.initials: PK
authors.lastname: Cunningham
authors.forename: R G
authors.initials: RG
authors.lastname: Smith
mesh_terms: 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
chemical_list: D001552:Benzazepines; D008782:Methylurea Compounds; D013777:Tetrazoles; C081455:L 692429; D013006:Growth Hormone; C112108:L 739943