Discovery of potent and orally bioavailable heterocycle-based cannabinoid CB1 receptor agonists

Takao Kiyoi; Julia M Adam; John K Clark; Keneth Davies; Anna-Marie Easson; Darren Edwards; Helen Feilden; Ruth Fields; Stuart Francis; Fiona Jeremiah; Duncan McArthur; Angus J Morrison; Alan Prosser; Paul D Ratcliffe; Jurgen Schulz; Grant Wishart; James Baker; Robert Campbell; Jean E Cottney; Maureen Deehan; Ola Epemolu; Louise Evans

doi:10.1016/j.bmcl.2011.01.082

Discovery of potent and orally bioavailable heterocycle-based cannabinoid CB1 receptor agonists

Takao Kiyoi, Julia M Adam, John K Clark, Keneth Davies, Anna-Marie Easson, Darren Edwards, Helen Feilden, Ruth Fields, Stuart Francis, Fiona Jeremiah, Duncan McArthur, Angus J Morrison, Alan Prosser, Paul D Ratcliffe, Jurgen Schulz, Grant Wishart, James Baker, Robert Campbell, Jean E Cottney, Maureen DeehanOla Epemolu, Louise Evans

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

6 Citations (Scopus)

Abstract

Novel 3-(1H-indol-3-yl)-1,2,4-oxadiazoles and -thiadiazoles were synthesized and found to be potent CB1 cannabinoid receptor agonists. The oral bioavailability of these compounds could be dramatically improved by optimization studies of the side chains attached to the indole and oxadiazole cores, leading to identification of a CB1 receptor agonist with good oral activity in a range of preclinical models of antinociception and antihyperalgesia.

Original language	English
Pages (from-to)	1748-1753
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	21
Issue number	6
DOIs	https://doi.org/10.1016/j.bmcl.2011.01.082
Publication status	Published - 15 Mar 2011

Keywords

administration, oral
animals
biological availability
drug discovery
heterocyclic compounds
rats
receptor, cannabinoid, CB1

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10.1016/j.bmcl.2011.01.082

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Kiyoi, T., Adam, J. M., Clark, J. K., Davies, K., Easson, A-M., Edwards, D., Feilden, H., Fields, R., Francis, S., Jeremiah, F., McArthur, D., Morrison, A. J., Prosser, A., Ratcliffe, P. D., Schulz, J., Wishart, G., Baker, J., Campbell, R., Cottney, J. E., ... Evans, L. (2011). Discovery of potent and orally bioavailable heterocycle-based cannabinoid CB1 receptor agonists. Bioorganic and Medicinal Chemistry Letters, 21(6), 1748-1753. https://doi.org/10.1016/j.bmcl.2011.01.082

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title = "Discovery of potent and orally bioavailable heterocycle-based cannabinoid CB1 receptor agonists",

abstract = "Novel 3-(1H-indol-3-yl)-1,2,4-oxadiazoles and -thiadiazoles were synthesized and found to be potent CB1 cannabinoid receptor agonists. The oral bioavailability of these compounds could be dramatically improved by optimization studies of the side chains attached to the indole and oxadiazole cores, leading to identification of a CB1 receptor agonist with good oral activity in a range of preclinical models of antinociception and antihyperalgesia.",

keywords = "administration, oral, animals, biological availability, drug discovery, heterocyclic compounds, rats, receptor, cannabinoid, CB1",

author = "Takao Kiyoi and Adam, {Julia M} and Clark, {John K} and Keneth Davies and Anna-Marie Easson and Darren Edwards and Helen Feilden and Ruth Fields and Stuart Francis and Fiona Jeremiah and Duncan McArthur and Morrison, {Angus J} and Alan Prosser and Ratcliffe, {Paul D} and Jurgen Schulz and Grant Wishart and James Baker and Robert Campbell and Cottney, {Jean E} and Maureen Deehan and Ola Epemolu and Louise Evans",

year = "2011",

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doi = "10.1016/j.bmcl.2011.01.082",

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Kiyoi, T, Adam, JM, Clark, JK, Davies, K, Easson, A-M, Edwards, D, Feilden, H, Fields, R, Francis, S, Jeremiah, F, McArthur, D, Morrison, AJ, Prosser, A, Ratcliffe, PD, Schulz, J, Wishart, G, Baker, J, Campbell, R, Cottney, JE, Deehan, M, Epemolu, O & Evans, L 2011, 'Discovery of potent and orally bioavailable heterocycle-based cannabinoid CB1 receptor agonists', Bioorganic and Medicinal Chemistry Letters, vol. 21, no. 6, pp. 1748-1753. https://doi.org/10.1016/j.bmcl.2011.01.082

TY - JOUR

T1 - Discovery of potent and orally bioavailable heterocycle-based cannabinoid CB1 receptor agonists

AU - Kiyoi, Takao

AU - Adam, Julia M

AU - Clark, John K

AU - Davies, Keneth

AU - Easson, Anna-Marie

AU - Edwards, Darren

AU - Feilden, Helen

AU - Fields, Ruth

AU - Francis, Stuart

AU - Jeremiah, Fiona

AU - McArthur, Duncan

AU - Morrison, Angus J

AU - Prosser, Alan

AU - Ratcliffe, Paul D

AU - Schulz, Jurgen

AU - Wishart, Grant

AU - Baker, James

AU - Campbell, Robert

AU - Cottney, Jean E

AU - Deehan, Maureen

AU - Epemolu, Ola

AU - Evans, Louise

PY - 2011/3/15

Y1 - 2011/3/15

N2 - Novel 3-(1H-indol-3-yl)-1,2,4-oxadiazoles and -thiadiazoles were synthesized and found to be potent CB1 cannabinoid receptor agonists. The oral bioavailability of these compounds could be dramatically improved by optimization studies of the side chains attached to the indole and oxadiazole cores, leading to identification of a CB1 receptor agonist with good oral activity in a range of preclinical models of antinociception and antihyperalgesia.

AB - Novel 3-(1H-indol-3-yl)-1,2,4-oxadiazoles and -thiadiazoles were synthesized and found to be potent CB1 cannabinoid receptor agonists. The oral bioavailability of these compounds could be dramatically improved by optimization studies of the side chains attached to the indole and oxadiazole cores, leading to identification of a CB1 receptor agonist with good oral activity in a range of preclinical models of antinociception and antihyperalgesia.

KW - administration, oral

KW - animals

KW - biological availability

KW - drug discovery

KW - heterocyclic compounds

KW - rats

KW - receptor, cannabinoid, CB1

UR - http://www.journals.elsevier.com/bioorganic-and-medicinal-chemistry-letters

U2 - 10.1016/j.bmcl.2011.01.082

DO - 10.1016/j.bmcl.2011.01.082

M3 - Article

C2 - 21316962

SN - 0960-894X

VL - 21

SP - 1748

EP - 1753

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 6

ER -

Discovery of potent and orally bioavailable heterocycle-based cannabinoid CB1 receptor agonists

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