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Structure–activity studies of a novel series of isoxazole-3-carboxamide derivatives as TRPV1 antagonists

2010; Elsevier BV; Volume: 21; Issue: 3 Linguagem: Inglês

10.1016/j.bmcl.2010.12.092

1464-3405

Ronald Palin, Lynn Abernethy, Nasrin Ansari, Kenneth S. Cameron, Tom Clarkson, Maureen Dempster, David A. Dunn, Anna-Marie Easson, Darren Edwards, John Maclean, Katy L. Everett, Helen Feilden, Koc-Kan Ho, Steve Kultgen, Peter Littlewood, Duncan McArthur, Deborah McGregor, Hazel McLuskey, Irina Neagu, S. Neale, Lesley-Anne Nisbet, Michael Ohlmeyer, Quynhchi Pham, Paul Ratcliffe, Yajing Rong, Andrew L. Roughton, Melanie Sammons, R. N. Swanson, Heather Tracey, Glenn Walker,

Thermoregulation and physiological responses

Optimisation of a screening hit incorporating both TRPV1 activity and solubility was conducted. Substitution of the isoxazole-3-carboxamide with the bespoke 1S, 3R-3-aminocyclohexanol motif afforded the requisite balance of potency and solubility. Compounds 32 and 40 were found to have antihyperalgesic effects in the rat CFA Hg assay and induce a mechanism based hyperthermia.