Metabolics Pharma, Inc.

ENT-03 was predicted to be the mammalian equivalent of trodusquemine, based on knowledge of the bile acids produced in mammals, such as 7-HOCA.The individual C-25 isomers of ENT-03 were prepared and both isomers were detected in neonatal mouse brain and liver.Trodusquemine and ENT-03 have both demonstrated dramatic effects in obesity and insulin resistance. (25S)-ENT-03 was selected for development for the treatment of diabetes and obesity.In this paper the first synthesis of this putative natural product is described.Starting with a stereo-defined steroidal intermediate 2, the semi-synthesis involves three stereoselective steps: Horner-Emmons olefination, hydrogenation, and reductive amination.Asym. hydrogenation using a ruthenium coordinated Mandyphos ligand was found to be effective in controlling the C25-stereochem. of both isomers.The syntheses of the ENT-03 isomers and a deuterated reference standard facilitated identification and quantification of this natural product in mouse tissues, and exploration of its therapeutic potential.