Identification and hit-to-lead optimization of a novel class of CB1 antagonists

Jeffrey J Letourneau; Patrick Jokiel; John Olson; Christopher M Riviello; Koc-Kan Ho; Lihong McAleer; Jingchun Yang; Robert N Swanson; James Baker; Phillip Cowley; Darren Edwards; Nick Ward; Michael H J Ohlmeyer; Maria L Webb

doi:10.1016/j.bmcl.2010.07.091

Identification and hit-to-lead optimization of a novel class of CB1 antagonists

Jeffrey J Letourneau, Patrick Jokiel, John Olson, Christopher M Riviello, Koc-Kan Ho, Lihong McAleer, Jingchun Yang, Robert N Swanson, James Baker, Phillip Cowley, Darren Edwards, Nick Ward, Michael H J Ohlmeyer, Maria L Webb

Strathclyde Institute Of Pharmacy And Biomedical Sciences

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

3 Citations (Scopus)

Abstract

The discovery, synthesis and preliminary structure-activity relationships (SARs) of a novel class of CB1 antagonists is described. Initial optimization of benzimidazole-based screening hit 4 led to the identification of 'inverted' indole-based lead compound 18c with improved properties versus compound 4 including reduced AlogP, improved microsomal stability and improved aqueous solubility. Compound 18c demonstrates in vivo CB1 antagonist efficacy (CB1 agonist induced hypothermia model) and is orally bioavailable in rat.

Original language	English
Pages (from-to)	5449-5453
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	20
Issue number	18
DOIs	https://doi.org/10.1016/j.bmcl.2010.07.091
Publication status	Published - 15 Sept 2010

Keywords

animals
benzimidazoles
humans
hypothermia
indoles
mice
microsomes, liver
obesity
rats
rats, wistar
receptor, Cannabinoid, CB1
solubility
structure-activity relationships

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmcl.2010.07.091

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Letourneau, J. J., Jokiel, P., Olson, J., Riviello, C. M., Ho, K.-K., McAleer, L., Yang, J., Swanson, R. N., Baker, J., Cowley, P., Edwards, D., Ward, N., Ohlmeyer, M. H. J., & Webb, M. L. (2010). Identification and hit-to-lead optimization of a novel class of CB1 antagonists. Bioorganic and Medicinal Chemistry Letters, 20(18), 5449-5453. https://doi.org/10.1016/j.bmcl.2010.07.091

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title = "Identification and hit-to-lead optimization of a novel class of CB1 antagonists",

abstract = "The discovery, synthesis and preliminary structure-activity relationships (SARs) of a novel class of CB1 antagonists is described. Initial optimization of benzimidazole-based screening hit 4 led to the identification of 'inverted' indole-based lead compound 18c with improved properties versus compound 4 including reduced AlogP, improved microsomal stability and improved aqueous solubility. Compound 18c demonstrates in vivo CB1 antagonist efficacy (CB1 agonist induced hypothermia model) and is orally bioavailable in rat.",

keywords = "animals, benzimidazoles, humans, hypothermia, indoles, mice, microsomes, liver, obesity, rats, rats, wistar, receptor, Cannabinoid, CB1, solubility, structure-activity relationships",

author = "Letourneau, {Jeffrey J} and Patrick Jokiel and John Olson and Riviello, {Christopher M} and Koc-Kan Ho and Lihong McAleer and Jingchun Yang and Swanson, {Robert N} and James Baker and Phillip Cowley and Darren Edwards and Nick Ward and Ohlmeyer, {Michael H J} and Webb, {Maria L}",

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day = "15",

doi = "10.1016/j.bmcl.2010.07.091",

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journal = "Bioorganic and Medicinal Chemistry Letters",

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T1 - Identification and hit-to-lead optimization of a novel class of CB1 antagonists

AU - Letourneau, Jeffrey J

AU - Jokiel, Patrick

AU - Olson, John

AU - Riviello, Christopher M

AU - Ho, Koc-Kan

AU - McAleer, Lihong

AU - Yang, Jingchun

AU - Swanson, Robert N

AU - Baker, James

AU - Cowley, Phillip

AU - Edwards, Darren

AU - Ward, Nick

AU - Ohlmeyer, Michael H J

AU - Webb, Maria L

PY - 2010/9/15

Y1 - 2010/9/15

N2 - The discovery, synthesis and preliminary structure-activity relationships (SARs) of a novel class of CB1 antagonists is described. Initial optimization of benzimidazole-based screening hit 4 led to the identification of 'inverted' indole-based lead compound 18c with improved properties versus compound 4 including reduced AlogP, improved microsomal stability and improved aqueous solubility. Compound 18c demonstrates in vivo CB1 antagonist efficacy (CB1 agonist induced hypothermia model) and is orally bioavailable in rat.

AB - The discovery, synthesis and preliminary structure-activity relationships (SARs) of a novel class of CB1 antagonists is described. Initial optimization of benzimidazole-based screening hit 4 led to the identification of 'inverted' indole-based lead compound 18c with improved properties versus compound 4 including reduced AlogP, improved microsomal stability and improved aqueous solubility. Compound 18c demonstrates in vivo CB1 antagonist efficacy (CB1 agonist induced hypothermia model) and is orally bioavailable in rat.

KW - animals

KW - benzimidazoles

KW - humans

KW - hypothermia

KW - indoles

KW - mice

KW - microsomes, liver

KW - obesity

KW - rats

KW - rats, wistar

KW - receptor, Cannabinoid, CB1

KW - solubility

KW - structure-activity relationships

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

U2 - 10.1016/j.bmcl.2010.07.091

DO - 10.1016/j.bmcl.2010.07.091

M3 - Article

C2 - 20719511

SN - 0960-894X

VL - 20

SP - 5449

EP - 5453

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 18

ER -

Identification and hit-to-lead optimization of a novel class of CB1 antagonists

Abstract

Keywords

UN SDGs

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