Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 58, Issue 8, Pages 3315-3328Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm500829b
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Funding
- National Science and Technology Major Project-Key New Drug Creation and Manufacturing program, China [2012ZX09103101-049]
- National Nature Science Foundation of China [81202571]
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Activation of TGR5 stimulates intestinal glucagon-like peptide-1 (GLP-1) release, but activation of the receptors in gallbladder and heart has been shown to cause severe on-target side effects. A series of low-absorbed TGR5 agonists was prepared by modifying compound 2 with polar functional groups to limit systemic exposure and specifically activate TGR5 in the intestine. Compound 15c, with a molecular weight of 1401, a PSA value of 223 angstrom(2), and low permeability on Caco-2 cells, exhibited satisfactory potency both in vitro and in vivo. Low levels of 15c were detected in blood, bile, and gallbladder tissue, and gallbladder-related side effects were substantially decreased compared to the absorbed small-molecule TGR5 agonist 2.
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