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Communication | Special issue | Vol 67, No. 2, 2006, pp.561-566
Published online, 11th November, 2005
DOI: 10.3987/COM-05-S(T)73
Novel Series of Highly Potent Non-peptide Growth Hormone Secretagogues with Improved Bioavailability

Hirohide Ishige,* Nobuo Ishiyama, Mitsuo Mimura, Mitsuo Hayashida, Tadashi Okuno, Kiyoharu Ukai, Takeshi Kiyofuji, Yasuo Yoneda, Shinji Tauchi, Akinori Aoyama, and Kiyoshi Inoguchi

*Central Research Institute, Kaken Pharmaceutical Co., Ltd., Shinomiya, Minamikawara-cho, Yamashina-ku, Kyoto 607-8042, Japan


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 (ED50=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-dimethylpropionyl)pyrrolidine-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.