Selective cannabinoid receptor type 2 (CB2) agonists: Optimization of a series of purines leading to the identification of a clinical candidate for the treatment of osteoarthritic pain

Sean P. Hollinshead, Michael W. Tidwell, John Palmer, Rossella Guidetti, Adam Sanderson, Michael P. Johnson, Mark G. Chambers, Jennifer Oskins, Robert Stratford Jr., Peter C. Astles

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

A focused screening strategy identified thienopyrimidine 12 as a cannabinoid receptor type 2 agonist (hCB2) with moderate selectivity over the hCB1 receptor. This initial hit suffered from poor in vitro metabolic stability and high in vivo clearance. Structure-activity relationships describe the optimization and modification to a new more polar series of purine CB2 agonists. Examples from this novel scaffold were found to be highly potent and fully efficacious agonists of the human CB2 receptor with excellent selectivity against CB1, often having no CB1 agonist activity at the highest concentration measured (>100 μM). Compound 26 is a centrally penetrant molecule which possesses good biopharmaceutical properties, is highly water-soluble, and demonstrates robust oral activity in rodent models of joint pain. In addition, the peripherally restricted molecule 22 also demonstrated significant efficacy in the same analgesic model of rodent inflammatory pain.

Original languageEnglish (US)
Pages (from-to)5722-5733
Number of pages12
JournalJournal of Medicinal Chemistry
Volume56
Issue number14
DOIs
StatePublished - Jul 25 2013
Externally publishedYes

Fingerprint

Cannabinoid Receptor CB2
Purines
Rodentia
Cannabinoid Receptor Agonists
Pain
Arthralgia
Structure-Activity Relationship
Analgesics
Water
Therapeutics
thienopyrimidine
In Vitro Techniques
purine
3-(5-nitrofuryl)-7-(5-nitrofurfurylidene)-3,3a,4,5,6,7-hexahydro-2H-indazole

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Selective cannabinoid receptor type 2 (CB2) agonists : Optimization of a series of purines leading to the identification of a clinical candidate for the treatment of osteoarthritic pain. / Hollinshead, Sean P.; Tidwell, Michael W.; Palmer, John; Guidetti, Rossella; Sanderson, Adam; Johnson, Michael P.; Chambers, Mark G.; Oskins, Jennifer; Stratford Jr., Robert; Astles, Peter C.

In: Journal of Medicinal Chemistry, Vol. 56, No. 14, 25.07.2013, p. 5722-5733.

Research output: Contribution to journalArticle

Hollinshead, Sean P. ; Tidwell, Michael W. ; Palmer, John ; Guidetti, Rossella ; Sanderson, Adam ; Johnson, Michael P. ; Chambers, Mark G. ; Oskins, Jennifer ; Stratford Jr., Robert ; Astles, Peter C. / Selective cannabinoid receptor type 2 (CB2) agonists : Optimization of a series of purines leading to the identification of a clinical candidate for the treatment of osteoarthritic pain. In: Journal of Medicinal Chemistry. 2013 ; Vol. 56, No. 14. pp. 5722-5733.
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