Novel Series of Highly Potent Non-peptide Growth Hormone Secretagogues with Im- proved Bioavailability

The discovery and the SAR of acylproline derivatives as highly potent growth hormone secretagogues (GHSs) with good oral bioavailability are described. One representative compound, N-[3-(2,2-dimethylpropylamino)-2hydroxypropyl]-2(R)-[ 1-(2,2-dimethylpropionyl)pyrrolidine-2(S)-carbonylamino]3-naphthalen-2-ylpropionamide (4e), showed potent GHS activity (ED50=1 nM) and good oral bioavailability (BA=33.2%). Moreover, the optically pure N-[3-(2,2-dimethylpropylamino)-2(S)-hydroxypropyl]-2(R)-[ I -(2,2-dimethylpropionyl)pyrrolidine-2(S)-carbonylamino]-3-naphthalen-2-ylpropionamide ((2S)-4c) showed a good metabolic stability against in vitro clearance (human liver microsome) with potent GHS activity.