A novel series of 7-alkylidenyltetrahydroindazole-based acylsulfonamides were discovered as potent EP3 antagonists. The initial lead compound exhibited potent in vitro EP3 inhibitory activity and good selectivity against other EP receptors. In addition, compound demonstrated in vivo activity in a rat ivGTT model, reversing the suppressive effect of the EP3-specific agonist sulprostone on glucose-stimulated insulin secretion. Further optimization to improve the pharmacokinetic profile led to the discovery of compounds and with potent in vitro activity and significantly lower in vivo clearance and higher oral exposure than compound .
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8762748 | PMC |
| http://dx.doi.org/10.1021/acsmedchemlett.1c00594 | DOI Listing |
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