Oxindole derivatives as orally active potent growth hormone secretagogues

  • J Med Chem. 2001 Dec 20;44(26):4641-9. doi: 10.1021/jm0103763.
T Tokunaga  1 ,  W E Hume ,  T Umezome ,  K Okazaki ,  Y Ueki ,  K Kumagai ,  S Hourai ,  J Nagamine ,  H Seki ,  M Taiji ,  H Noguchi ,  R Nagata
Affiliations
  • 1. Research Division, Sumitomo Pharmaceuticals Co., Ltd, 1-98 Kasugadenaka 3-chome, Konohana-ku, Osaka 554-0022, Japan.
PMID: 11741481 DOI: 10.1021/jm0103763
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.