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

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

doi:10.1016/j.bmcl.2011.01.051

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

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

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

15 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	4652-4657
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	21
Issue number	15
DOIs	https://doi.org/10.1016/j.bmcl.2011.01.051
State	Published - 1 Aug 2011
Externally published	Yes

Keywords

Antihyperalgesia
Isoxazoles
TRPV1 antagonist

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10.1016/j.bmcl.2011.01.051

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Ratcliffe, P., Abernethy, L., Ansari, N., Cameron, K., Clarkson, T., Dempster, M., Dunn, D., Easson, A. M., Edwards, D., Everett, K., Feilden, H., Ho, K. K., Kultgen, S., Littlewood, P., MacLean, J., McArthur, D., McGregor, D., McLuskey, H., Neagu, I., ... Walker, G. (2011). Discovery of potent, soluble and orally active TRPV1 antagonists. Structure-activity relationships of a series of isoxazoles. Bioorganic and Medicinal Chemistry Letters, 21(15), 4652-4657. https://doi.org/10.1016/j.bmcl.2011.01.051

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title = "Discovery of potent, soluble and orally active TRPV1 antagonists. Structure-activity relationships of a series of isoxazoles",

abstract = "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.",

keywords = "Antihyperalgesia, Isoxazoles, TRPV1 antagonist",

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

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doi = "10.1016/j.bmcl.2011.01.051",

language = "English",

volume = "21",

pages = "4652--4657",

journal = "Bioorganic and Medicinal Chemistry Letters",

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Ratcliffe, P, Abernethy, L, Ansari, N, Cameron, K, Clarkson, T, Dempster, M, Dunn, D, Easson, AM, Edwards, D, Everett, K, Feilden, H, Ho, KK, Kultgen, S, Littlewood, P, MacLean, J, McArthur, D, McGregor, D, McLuskey, H, Neagu, I, Nimz, O, Nisbet, LA, Ohlmeyer, M, Palin, R, Pham, Q, Rong, Y, Roughton, A, Sammons, M, Swanson, R, Tracey, H & Walker, G 2011, 'Discovery of potent, soluble and orally active TRPV1 antagonists. Structure-activity relationships of a series of isoxazoles', Bioorganic and Medicinal Chemistry Letters, vol. 21, no. 15, pp. 4652-4657. https://doi.org/10.1016/j.bmcl.2011.01.051

TY - JOUR

T1 - Discovery of potent, soluble and orally active TRPV1 antagonists. Structure-activity relationships of a series of isoxazoles

AU - Ratcliffe, Paul

AU - Abernethy, Lynn

AU - Ansari, Nasrin

AU - Cameron, Ken

AU - Clarkson, Tom

AU - Dempster, Maureen

AU - Dunn, David

AU - Easson, Anna Marie

AU - Edwards, Darren

AU - Everett, Katy

AU - Feilden, Helen

AU - Ho, Koc Kan

AU - Kultgen, Steve

AU - Littlewood, Peter

AU - MacLean, John

AU - McArthur, Duncan

AU - McGregor, Deborah

AU - McLuskey, Hazel

AU - Neagu, Irina

AU - Nimz, Olaf

AU - Nisbet, Lesley Anne

AU - Ohlmeyer, Michael

AU - Palin, Ronnie

AU - Pham, Quynhchi

AU - Rong, Yajing

AU - Roughton, Andrew

AU - Sammons, Melanie

AU - Swanson, Robert

AU - Tracey, Heather

AU - Walker, Glenn

PY - 2011/8/1

Y1 - 2011/8/1

N2 - 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.

AB - 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.

KW - Antihyperalgesia

KW - Isoxazoles

KW - TRPV1 antagonist

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AN - SCOPUS:79960371480

SN - 0960-894X

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EP - 4657

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 15

ER -

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

Abstract

Keywords

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