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.
Optimization of a water soluble, moderately potent lead series of isoxazole-3-carboxamides was conducted, affording a compound with the requisite balance of potency, solubility and physicochemical properties for in vivo use. Compound 8e was demonstrated to be efficacious in a rat model of inflammatory pain, following oral administration.
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.
John Maclean合作论文数3Glenn Walker合作论文数3Helen Feilden合作论文数3Tom Clarkson合作论文数3Duncan Mcarthur合作论文数Department of Psychology, Georgia State University3Hazel Mcluskey合作论文数3Lesley-Anne Nisbet合作论文数3Paul D. Ratcliffe合作论文数3Anna-Marie Easson合作论文数3Deborah McGregor合作论文数3Darren Edwards合作论文数3Heather Tracey合作论文数3Maureen Dempster合作论文数3Lynn Abernethy合作论文数3Robert Swanson合作论文数2Yajing Rong合作论文数2Nasrin Ansari合作论文数2Quynhchi Pham合作论文数2Michael Ohlmeyer合作论文数2
David A Dunn合作论文数Dept Chem Engn, Auburn Univ2Roughton Andrew合作论文数2Olaf Nimz合作论文数2Koc-Kan Ho合作论文数2Melanie Sammons合作论文数2Ronnie Palin合作论文数2Steve Kultgen合作论文数2Ken Cameron合作论文数1Ronald Palin合作论文数1Stuart Neale合作论文数1Rachel Milne合作论文数1Kenneth Cameron合作论文数1
