Abstract
In the framework of the design and development of TGR5 agonists, we reported that the introduction of a C(23)(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 6alpha-ethyl-23(S)-methylcholic acid (S-EMCA, INT-777) as a novel potent and selective TGR5 agonist with remarkable in vivo activity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CHO Cells
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COS Cells
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Chlorocebus aethiops
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Cholic Acids / chemistry
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Cholic Acids / pharmacokinetics
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Cholic Acids / pharmacology*
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Cricetinae
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Cricetulus
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Diabetes Mellitus / drug therapy
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Humans
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Obesity / drug therapy
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Rats
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Receptors, G-Protein-Coupled / agonists*
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Receptors, G-Protein-Coupled / metabolism
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Stereoisomerism
Substances
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6alpha-ethyl-23(S)-methylcholic acid
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Cholic Acids
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GPBAR1 protein, human
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Receptors, G-Protein-Coupled