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
| Autor: | John Palmer, Michael P. Johnson, J.L. Oskins, Sean P. Hollinshead, Adam J. Sanderson, Peter C. Astles, Robert E. Stratford, Tidwell Michael Wade, Mark Chambers, Rossella Guidetti |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Agonist Cannabinoid receptor medicine.drug_class medicine.medical_treatment Analgesic Pharmacology Receptor Cannabinoid CB2 Structure-Activity Relationship Dogs In vivo Osteoarthritis Drug Discovery medicine Cannabinoid receptor type 2 Animals Humans Structure–activity relationship Receptor Chemistry Rats HEK293 Cells Guanosine 5'-O-(3-Thiotriphosphate) Purines Rats Inbred Lew Molecular Medicine lipids (amino acids peptides and proteins) Cannabinoid |
| Zdroj: | Journal of Medicinal Chemistry. 56:5722-5733 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm400305d |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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