Pyrazolopyridazine alpha-2-delta-1 ligands for the treatment of neuropathic pain

James W Myatt; Mark P Healy; Gianpaolo S Bravi; Andrew Billinton; Christopher N Johnson; Kim L Matthews; Karamjit S Jandu; Wenjing Meng; Anne Hersey; David G Livermore; Clement B Douault; Jason Witherington; Rino A Bit; James E Rowedder; Jason D Brown; Nick M Clayton

doi:10.1016/j.bmcl.2010.05.026

Pyrazolopyridazine alpha-2-delta-1 ligands for the treatment of neuropathic pain

James W Myatt, Mark P Healy, Gianpaolo S Bravi, Andrew Billinton, Christopher N Johnson, Kim L Matthews, Karamjit S Jandu, Wenjing Meng, Anne Hersey, David G Livermore, Clement B Douault, Jason Witherington, Rino A Bit, James E Rowedder, Jason D Brown, Nick M Clayton

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

16 Citations (Scopus)

Abstract

Optimization of the novel alpha-2-delta-1 ligand 4 provided compounds 37 and 38 which have improved DMPK profiles, good in vivo analgesic activity and in vitro selectivity over alpha-2-delta-2. An in-house P-gp prediction programme and the MetaSite software package were used to help solve the specific problems of high P-gp efflux and high in vivo clearance.

Original language	English
Pages (from-to)	4683-8
Number of pages	6
Journal	Bioorganic & Medicinal Chemistry Letters
Volume	20
Issue number	15
DOIs	https://doi.org/10.1016/j.bmcl.2010.05.026
Publication status	Published - 1 Aug 2010

Keywords

Analgesics
Animals
Calcium Channel Blockers
Calcium Channels
Ligands
Neuralgia
P-Glycoprotein
Pyrazoles
Pyridazines
Pyridines
Rats
Structure-Activity Relationship

Access to Document

10.1016/j.bmcl.2010.05.026

Cite this

Myatt, J. W., Healy, M. P., Bravi, G. S., Billinton, A., Johnson, C. N., Matthews, K. L., Jandu, K. S., Meng, W., Hersey, A., Livermore, D. G., Douault, C. B., Witherington, J., Bit, R. A., Rowedder, J. E., Brown, J. D., & Clayton, N. M. (2010). Pyrazolopyridazine alpha-2-delta-1 ligands for the treatment of neuropathic pain. Bioorganic & Medicinal Chemistry Letters, 20(15), 4683-8. https://doi.org/10.1016/j.bmcl.2010.05.026

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title = "Pyrazolopyridazine alpha-2-delta-1 ligands for the treatment of neuropathic pain",

abstract = "Optimization of the novel alpha-2-delta-1 ligand 4 provided compounds 37 and 38 which have improved DMPK profiles, good in vivo analgesic activity and in vitro selectivity over alpha-2-delta-2. An in-house P-gp prediction programme and the MetaSite software package were used to help solve the specific problems of high P-gp efflux and high in vivo clearance.",

keywords = "Analgesics, Animals, Calcium Channel Blockers, Calcium Channels, Ligands, Neuralgia, P-Glycoprotein, Pyrazoles, Pyridazines, Pyridines, Rats, Structure-Activity Relationship",

author = "Myatt, {James W} and Healy, {Mark P} and Bravi, {Gianpaolo S} and Andrew Billinton and Johnson, {Christopher N} and Matthews, {Kim L} and Jandu, {Karamjit S} and Wenjing Meng and Anne Hersey and Livermore, {David G} and Douault, {Clement B} and Jason Witherington and Bit, {Rino A} and Rowedder, {James E} and Brown, {Jason D} and Clayton, {Nick M}",

year = "2010",

month = aug,

day = "1",

doi = "10.1016/j.bmcl.2010.05.026",

language = "English",

volume = "20",

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journal = "Bioorganic & Medicinal Chemistry Letters",

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publisher = "Elsevier",

number = "15",

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Myatt, JW, Healy, MP, Bravi, GS, Billinton, A, Johnson, CN, Matthews, KL, Jandu, KS, Meng, W, Hersey, A, Livermore, DG, Douault, CB, Witherington, J, Bit, RA, Rowedder, JE, Brown, JD & Clayton, NM 2010, 'Pyrazolopyridazine alpha-2-delta-1 ligands for the treatment of neuropathic pain', Bioorganic & Medicinal Chemistry Letters, vol. 20, no. 15, pp. 4683-8. https://doi.org/10.1016/j.bmcl.2010.05.026

TY - JOUR

T1 - Pyrazolopyridazine alpha-2-delta-1 ligands for the treatment of neuropathic pain

AU - Myatt, James W

AU - Healy, Mark P

AU - Bravi, Gianpaolo S

AU - Billinton, Andrew

AU - Johnson, Christopher N

AU - Matthews, Kim L

AU - Jandu, Karamjit S

AU - Meng, Wenjing

AU - Hersey, Anne

AU - Livermore, David G

AU - Douault, Clement B

AU - Witherington, Jason

AU - Bit, Rino A

AU - Rowedder, James E

AU - Brown, Jason D

AU - Clayton, Nick M

PY - 2010/8/1

Y1 - 2010/8/1

N2 - Optimization of the novel alpha-2-delta-1 ligand 4 provided compounds 37 and 38 which have improved DMPK profiles, good in vivo analgesic activity and in vitro selectivity over alpha-2-delta-2. An in-house P-gp prediction programme and the MetaSite software package were used to help solve the specific problems of high P-gp efflux and high in vivo clearance.

AB - Optimization of the novel alpha-2-delta-1 ligand 4 provided compounds 37 and 38 which have improved DMPK profiles, good in vivo analgesic activity and in vitro selectivity over alpha-2-delta-2. An in-house P-gp prediction programme and the MetaSite software package were used to help solve the specific problems of high P-gp efflux and high in vivo clearance.

KW - Analgesics

KW - Animals

KW - Calcium Channel Blockers

KW - Calcium Channels

KW - Ligands

KW - Neuralgia

KW - P-Glycoprotein

KW - Pyrazoles

KW - Pyridazines

KW - Pyridines

KW - Rats

KW - Structure-Activity Relationship

U2 - 10.1016/j.bmcl.2010.05.026

DO - 10.1016/j.bmcl.2010.05.026

M3 - Article

C2 - 20566291

VL - 20

SP - 4683

EP - 4688

JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

SN - 0960-894X

IS - 15

ER -