Lactams as prostanoid receptor ligands. Part 4: 2-Piperidones as selective EP4 receptor agonists |
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Authors: | Elworthy Todd R Brill Emma R Caires Christopher C Kim Woongki Lach Leang K Tracy Jahari Laurant Chiou San-San |
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Affiliation: | Roche Palo Alto, Department of Medicinal Chemistry, 3431 Hillview Avenue, Palo Alto, CA 94304-1397, USA. todd.elworthy@roche.com |
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Abstract: | 2-Piperidones were prepared bearing heptanoic acid or a thioether heptanoic acid at the 1-position as well as appropriately substituted at the 6-position to mimic the structure of prostaglandins. The stereochemical purity at the 6-position was determined to be 95% ee for an advanced synthetic intermediate. The 2-piperidones were identified as potent agonists at the EP4 prostanoid receptor. They displayed a high affinity (Ki 5-130 nM) at EP4 and subtype selectivity. |
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