AI Article Synopsis
- The research focused on optimizing a lead compound to enhance its mPGES-1 inhibitory activity and improve its ADME profile by making substitutions at specific positions.
- By replacing bromine in the lead compound with different groups, the phenyl group was found to be the most effective for strong inhibitory activity and favorable ADME characteristics.
- Ultimately, compound 39 emerged as the top candidate, demonstrating impressive mPGES-1 inhibition, potent cell activity, and excellent oral absorption in tests.
Article Abstract
To identify compounds with strong mPGES-1 inhibitory activity and clear in vitro ADME profile, we optimized the lead compound 1 by carrying our substitutions at the C(7)- and C(8)-positions. Replacement of the bromine atom of 1 with various substituents led to identification of the phenyl group as the best C(7)-substituent giving strong inhibitory activity with good in vitro ADME profile. Further SAR examination on both the C(2)- and the C(7)-phenyl groups provided compound 39 as the best candidate for further development. Compound 39 exhibited strong mPGES-1 inhibitory activity (IC50=4.1 nM), potent cell-based functional activity (IC50=33 nM) with good mPGES-1 selectivity (over 700-fold), excellent in vitro ADME profile, and good oral absorption in rat PK study.
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| http://dx.doi.org/10.1016/j.bmc.2013.03.069 | DOI Listing |
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