Discovery and Optimization of 7-Alkylidenyltetrahydroindazole-Based Acylsulfonamide EP3 Antagonists
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 ra...
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| Veröffentlicht in: | ACS medicinal chemistry letters 2022-01, Vol.13 (1), p.111-117 |
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| container_end_page | 117 |
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| container_title | ACS medicinal chemistry letters |
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| creator | Zhu, Bin Zhang, Xuqing Guo, Lili Rankin, Matthew Bakaj, Ivona Ho, George Lee, Seunghun P Norquay, Lisa Macielag, Mark |
| description | 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
. |
| doi_str_mv | 10.1021/acsmedchemlett.1c00594 |
| format | Article |
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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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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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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
.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>35059130</pmid><doi>10.1021/acsmedchemlett.1c00594</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0002-8821-7751</orcidid><orcidid>https://orcid.org/0000-0001-8996-2908</orcidid><orcidid>https://orcid.org/0000-0002-0085-6867</orcidid><oa>free_for_read</oa></addata></record> |
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| language | eng |
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| source | EZB-FREE-00999 freely available EZB journals; PubMed Central; American Chemical Society Journals |
| subjects | Letter |
| title | Discovery and Optimization of 7-Alkylidenyltetrahydroindazole-Based Acylsulfonamide EP3 Antagonists |
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