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Naphthalene/quinoline amides and sulfonylureas as potent and selective antagonists of the EP4 receptor |
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| Authors: | Burch Jason D Farand Julie Colucci John Sturino Claudio Ducharme Yves Friesen Richard W Lévesque Jean-François Gagné Sébastien Wrona Mark Therien Alex G Mathieu Marie-Claude Denis Danielle Vigneault Erika Xu Daigen Clark Patsy Rowland Steve Han Yongxin |
| Institution: | a Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, Merck Frosst Canada Ltd, 16711 Trans-Canada Hwy. Kirkland, Québec, Canada H9H 3L1 b Department of DMPK, Merck Frosst Centre for Therapeutic Research, Merck Frosst Canada Ltd, 16711 Trans-Canada Hwy. Kirkland, Québec, Canada H9H 3L1 c Department of In vitro Sciences, Merck Frosst Centre for Therapeutic Research, Merck Frosst Canada Ltd, 16711 Trans-Canada Hwy. Kirkland, Québec, Canada H9H 3L1 d Department of In vivo Sciences, Merck Frosst Centre for Therapeutic Research, Merck Frosst Canada Ltd, 16711 Trans-Canada Hwy. Kirkland, Québec, Canada H9H 3L1 |
| Abstract: | Two new series of EP4 antagonists based on naphthalene/quinoline scaffolds have been identified as part of our on-going efforts to develop treatments for inflammatory pain. One series contains an acidic sulfonylurea pharmacophore, whereas the other is a neutral amide. Both series show subnanomolar intrinsic binding potency towards the EP4 receptor, and excellent selectivity towards other prostanoid receptors. While the amide series generally displays poor pharmacokinetic parameters, the sulfonylureas exhibit greatly improved profile. MF-592, the optimal compound from the sulfonylurea series, has a desirable overall preclinical profile that suggests it is suitable for further development. |
| Keywords: | Naphthalene/quinoline amides and sulfonylureas EP4 receptor antagonist Inflammatory pain |
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