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Discovery of 6α-Ethyl-23(S)-methylcholic Acid (S-EMCA, INT-777) as a Potent and Selective Agonist for the TGR5 Receptor, a Novel Target for Diabesity

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journal contribution
posted on 24.12.2009, 00:00 by Roberto Pellicciari, Antimo Gioiello, Antonio Macchiarulo, Charles Thomas, Emiliano Rosatelli, Benedetto Natalini, Roccaldo Sardella, Mark Pruzanski, Aldo Roda, Elisabetta Pastorini, Kristina Schoonjans, Johan Auwerx
In the framework of the design and development of TGR5 agonists, we reported that the introduction of a C23(S)-methyl group in the side chain of bile acids such as chenodeoxycholic acid (CDCA) and 6-ethylchenodeoxycholic acid (6-ECDCA, INT-747) affords selectivity for TGR5. Herein we report further lead optimization efforts that have led to the discovery of 6α-ethyl-23(S)-methylcholic acid (S-EMCA, INT-777) as a novel potent and selective TGR5 agonist with remarkable in vivo activity.