NOVEL SERIES OF HIGHLY POTENT NON-PEPTIDE GROWTH HORMONE SECRETAGOGUES WITH IMPROVED BIOAVAILABILITY

摘要

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)-2-hydroxypropyl]-2(R)-[1-(2,2-dimethylpropionyl)pyrrolidine-2(S)-carbonylamino]-3-naphthalen-2-ylpropionamide(4e),showed potent GHS activity(ED_(50)=1 nM)and good oral bioavailability(BA=33.2%).Moreover,the optically pure N-[3-(2,2-dimethylpropylamino)-2(S)-hydroxypropyl]-2(R)-[1-(2,2-dimethylpro-pionyl)pyiTolidine-2(S)-carbonylamino]-3-naphthalen-2-ylpropionamide((2S)-4e)showed a good metabolic stability against in vitro clearance(human liver microsome)with potent GHS activity.