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

…, L Abernethy, N Ansari, K Cameron, T Clarkson…

Index: Palin, Ronald; Abernethy, Lynn; Ansari, Nasrin; Cameron, Kenneth; Clarkson, Tom; Dempster, Maureen; Dunn, David; Easson, Anna-Marie; Edwards, Darren; MacLean, John; Everett, Katy; Feilden, Helen; Ho, Koc-Kan; Kultgen, Steve; Littlewood, Peter; McArthur, Duncan; McGregor, Deborah; McLuskey, Hazel; Neagu, Irina; Neale, Stuart; Nisbet, Lesley-Anne; Ohlmeyer, Michael; Pham, Quynhchi; Ratcliffe, Paul; Rong, Yajing; Roughton, Andrew; Sammons, Melanie; Swanson, Robert; Tracey, Heather; Walker, Glenn Bioorganic and Medicinal Chemistry Letters, 2011 , vol. 21, # 3 p. 892 - 898

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Citation Number: 17

Abstract

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.