Discovery of potent, soluble and orally active TRPV1 antagonists. Structure–activity relationships of a series of isoxazoles

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 ra...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2011-08, Vol.21 (15), p.4652-4657
Hauptverfasser:	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
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Amides - chemistry Amides - pharmacokinetics Amides - therapeutic use Analgesics Animals Antihyperalgesia Biological and medical sciences Capsaicin - toxicity Cyclohexanols - chemistry Cyclohexanols - pharmacokinetics Cyclohexanols - therapeutic use Disease Models, Animal Drug Evaluation, Preclinical Humans Hyperalgesia - chemically induced Hyperalgesia - drug therapy Isoxazoles Isoxazoles - chemistry Isoxazoles - pharmacokinetics Isoxazoles - therapeutic use Medical sciences Microsomes, Liver - metabolism Neuropharmacology Pharmacology. Drug treatments Rats Structure-Activity Relationship TRPV Cation Channels - antagonists & inhibitors TRPV Cation Channels - metabolism TRPV1 antagonist
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Zusammenfassung:	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. 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.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2011.01.051