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Discovery of potent, soluble and orally active TRPV1 antagonists. Structure-activity relationships of a series of isoxazoles |
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| Authors: | Ratcliffe Paul Abernethy Lynn Ansari Nasrin Cameron Ken Clarkson Tom Dempster Maureen Dunn David Easson Anna-Marie Edwards Darren Everett Katy Feilden Helen Ho Koc-Kan Kultgen Steve Littlewood Peter Maclean John McArthur Duncan McGregor Deborah McLuskey Hazel Neagu Irina Nimz Olaf Nisbet Lesley-Anne Ohlmeyer Michael Palin Ronnie Pham Quynhchi Rong Yajing Roughton Andrew Sammons Melanie Swanson Robert Tracey Heather Walker Glenn |
| Affiliation: | a Merck Research Laboratories, MSD, Newhouse, Motherwell, Lanarkshire ML1 5SH, UK b Pharmacopeia, PO Box 5350, Princeton, NJ 08543, United States |
| Abstract: | Systematic optimisation of a poorly soluble lead series of isoxazole-3-carboxamides was conducted. Substitution of the 4-position with specific polar functionality afforded the requisite balance of potency, solubility and physicochemical properties. Compound 21a was found to be efficacious in the rat Capsaicin Hargreaves assay following oral administration. |
| Keywords: | TRPV1 antagonist Antihyperalgesia Isoxazoles |
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