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

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

doi:10.1016/j.bmcl.2010.12.092

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

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

Research output: Contribution to journal › Article › peer-review

23 Scopus citations

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.

Original language	English
Pages (from-to)	892-898
Number of pages	7
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	21
Issue number	3
DOIs	https://doi.org/10.1016/j.bmcl.2010.12.092
State	Published - 1 Feb 2011
Externally published	Yes

Keywords

Antihyperalgesia
Hyperthermia
Isoxazoles
TRPV1 antagonist

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10.1016/j.bmcl.2010.12.092

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Palin, R., Abernethy, L., Ansari, N., Cameron, K., Clarkson, T., Dempster, M., Dunn, D., Easson, A. M., Edwards, D., MacLean, J., Everett, K., Feilden, H., Ho, K. K., Kultgen, S., Littlewood, P., McArthur, D., McGregor, D., McLuskey, H., Neagu, I., ... Walker, G. (2011). Structure-activity studies of a novel series of isoxazole-3-carboxamide derivatives as TRPV1 antagonists. Bioorganic and Medicinal Chemistry Letters, 21(3), 892-898. https://doi.org/10.1016/j.bmcl.2010.12.092

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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.",

keywords = "Antihyperalgesia, Hyperthermia, Isoxazoles, TRPV1 antagonist",

author = "Ronald Palin and Lynn Abernethy and Nasrin Ansari and Kenneth Cameron and Tom Clarkson and Maureen Dempster and David Dunn and Easson, {Anna Marie} and Darren Edwards and John MacLean and Katy Everett and Helen Feilden and Ho, {Koc Kan} and Steve Kultgen and Peter Littlewood and Duncan McArthur and Deborah McGregor and Hazel McLuskey and Irina Neagu and Stuart Neale and Nisbet, {Lesley Anne} and Michael Ohlmeyer and Quynhchi Pham and Paul Ratcliffe and Yajing Rong and Andrew Roughton and Melanie Sammons and Robert Swanson and Heather Tracey and Glenn Walker",

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Palin, R, Abernethy, L, Ansari, N, Cameron, K, Clarkson, T, Dempster, M, Dunn, D, Easson, AM, Edwards, D, MacLean, J, Everett, K, Feilden, H, Ho, KK, Kultgen, S, Littlewood, P, McArthur, D, McGregor, D, McLuskey, H, Neagu, I, Neale, S, Nisbet, LA, Ohlmeyer, M, Pham, Q, Ratcliffe, P, Rong, Y, Roughton, A, Sammons, M, Swanson, R, Tracey, H & Walker, G 2011, 'Structure-activity studies of a novel series of isoxazole-3-carboxamide derivatives as TRPV1 antagonists', Bioorganic and Medicinal Chemistry Letters, vol. 21, no. 3, pp. 892-898. https://doi.org/10.1016/j.bmcl.2010.12.092

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AU - Palin, Ronald

AU - Abernethy, Lynn

AU - Ansari, Nasrin

AU - Cameron, Kenneth

AU - Clarkson, Tom

AU - Dempster, Maureen

AU - Dunn, David

AU - Easson, Anna Marie

AU - Edwards, Darren

AU - MacLean, John

AU - Everett, Katy

AU - Feilden, Helen

AU - Ho, Koc Kan

AU - Kultgen, Steve

AU - Littlewood, Peter

AU - McArthur, Duncan

AU - McGregor, Deborah

AU - McLuskey, Hazel

AU - Neagu, Irina

AU - Neale, Stuart

AU - Nisbet, Lesley Anne

AU - Ohlmeyer, Michael

AU - Pham, Quynhchi

AU - Ratcliffe, Paul

AU - Rong, Yajing

AU - Roughton, Andrew

AU - Sammons, Melanie

AU - Swanson, Robert

AU - Tracey, Heather

AU - Walker, Glenn

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KW - Antihyperalgesia

KW - Hyperthermia

KW - Isoxazoles

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JF - Bioorganic and Medicinal Chemistry Letters

IS - 3

ER -

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

Abstract

Keywords

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