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.
Supplementary Material Available:A listing of positional and thermal parameters, and tables of bond lengths and angles for (+)-2, the dicamphorsulfonate of (lS,2S,4S,5S)-2,5-diphenylcyclohexane-1 &diol, and (f)-Cp*CpTiCI2, including SHELXTL renditions of the structures of the latter two compounds (16 pages); tables of observed and calculated structure factors for the three previously listed compounds (34 pages). Ordering information is given on any current masthead page.(1 5) This picture presupposes that the stereochemistry of hydrogenation is set at this stage, an assumption which may not be valid: Halpern, J. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: Orlando, F1, 1985; Vol. 5, p 41. Indeed, the mechanism of this process has not been established. See, also: Lehmkuhl, H.; Tsien, Y.-L.; Janssen, E.; Mynott, R. Chem. Ber. 1983, 116, 2426 (1 6) An X-ray structural analysis of this compound (in the racemic series) reveals the openness of one of the metal faces to a nonstereodifferentiating substrate approach (see Supplementary Material).
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