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
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.
Hollinshead, Sean P.,Tidwell, Michael W.,Palmer, John,Guidetti, Rossella,Sanderson, Adam,Johnson, Michael P.,Chambers, Mark G.,Oskins, Jennifer,Stratford, Robert,Astles, Peter C.
p. 5722 - 5733
(2013/08/23)
Discovery and optimization of novel purines as potent and selective CB2 agonists
A focused screening strategy identified thienopyrimidine 1 as a hCB2 cannabinoid receptor agonist 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 less lipophilic purine core. Examples from this novel series were found to be highly potent and fully efficacious agonists of the human CB2 receptor with excellent selectivity against CB1. Compound 10 possesses good biopharmaceutical properties, is highly water soluble and demonstrates robust oral activity in rodent models of joint pain.
Hollinshead, Sean P.,Astles, Peter C.,Chambers, Mark G.,Johnson, Michael P.,Palmer, John,Tidwell, Michael W.
scheme or table
p. 4962 - 4966
(2012/09/07)
PURINE COMPOUNDS USED AS CB2 AGONISTS
A compound of the formula (I) and pharmaceutical compositions for the treatment of pain.
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Page/Page column 13
(2011/10/13)
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