title: Oxindole derivatives as orally active potent growth hormone secretagogues.
abstract: A series of substituted oxindole derivatives was synthesized and evaluated for growth hormone (GH) releasing activity using cultured rat pituitary cells. (+)-6-Carbamoyl-3-(2-chlorophenyl)-(2-diethylaminoethyl)-4-trifluoromethyloxindole (SM-130686, 37S) was found to have potent activity (EC(50) = 3.0 nM), while the other enantiomer 37R had reduced activity. The absolute configuration of 37S was confirmed by X-ray crystallographic analysis. Compound 37S showed a good pharmacokinetic profile in rats with 28% oral bioavailability at 10 mg/kg and excellent in vivo activity as evidenced by a significant weight gain after 4 days of oral administration at 10 mg/kg twice a day. Compound 37S displaced the binding of (35)S-MK-677 to human GHS-R with an IC(50) value of 1.2 +/- 0.2 nM.
authors.affiliation: Research Division, Sumitomo Pharmaceuticals Co., Ltd, 1-98 Kasugadenaka 3-chome, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Tokunaga
authors.forename: W E
authors.initials: WE
authors.lastname: Hume
authors.forename: T
authors.initials: T
authors.lastname: Umezome
authors.forename: K
authors.initials: K
authors.lastname: Okazaki
authors.forename: Y
authors.initials: Y
authors.lastname: Ueki
authors.forename: K
authors.initials: K
authors.lastname: Kumagai
authors.forename: S
authors.initials: S
authors.lastname: Hourai
authors.forename: J
authors.initials: J
authors.lastname: Nagamine
authors.forename: H
authors.initials: H
authors.lastname: Seki
authors.forename: M
authors.initials: M
authors.lastname: Taiji
authors.forename: H
authors.initials: H
authors.lastname: Noguchi
authors.forename: R
authors.initials: R
authors.lastname: Nagata
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001835:Body Weight / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D018360:Crystallography, X-Ray; D005021:Ethylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D013006:Growth Hormone / Q000378:metabolism*; D019382:Human Growth Hormone / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D010903:Pituitary Gland, Anterior / Q000166:cytology / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D005021:Ethylamines; D007211:Indoles; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; C443685:SM 130686; D019382:Human Growth Hormone; D013006:Growth Hormone