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. |