New 1,2,3,4-tetrahydropyrrolo[3,4-b]indole derivatives as selective CB2 receptor agonists Daniel Page ´, a, * Hua Yang, a William Brown, a Christopher Walpole, a Manon Fleurent, b Meredith Fyfe, b Franc ¸ois Gaudreault b and Ste ´phane St-Onge b a Department of Medicinal Chemistry, AstraZeneca R&D Montreal, St-Laurent, Que., Canada H4S 1Z9 b Department of Molecular Pharmacology, AstraZeneca R&D Montreal, 7171 Frederick-Banting, St-Laurent, Que., Canada H4S 1Z9 Received 31 July 2007; revised 4 September 2007; accepted 5 September 2007 Available online 8 September 2007 Abstract—The preparation and evaluation of a novel class of CB2 agonists based on a 1,2,3,4-tetrahydropyrrolo[3,4-b]indole moiety are reported. They showed binding affinities up to 4.2 nM toward CB2 with sub-nanomolar EC 50 values. They also showed mod- erate to good (>350-fold) selectivity over the CB1 receptor. Ó 2007 Elsevier Ltd. All rights reserved. The endocannabinoid system has been known to medi- ate several important biological processes including met- abolic regulation, 1,2 pain, 3–5 cellular proliferation, 6 cancer, 7 obesity, 8 and different other CNS functions. 9 These effects are mainly regulated via two primary receptors, namely CB1 and CB2. The pharmacology of these two cannabinoid receptors has been extensively reviewed 10–14 over the past few years, putting a much larger emphasis on the more studied CB1 receptor, resulting in huge commercial interests in CB1 receptor ligands. CB1 antagonists are now being evaluated for the treatment of obesity, metabolic syndrome, drug abuse, and smoking cessation, 2 while CB1 agonists are currently in clinical trials for the treatment of acute and chronic pain. 3–5 However, because the CB1 receptor is mainly expressed in the central nervous system, sev- eral psychoactive side effects 15–17 such as cognitive dis- function, motor incoordination, or sedation have often been associated with CB1 ligands. On the other hand, the exact physiological roles of the CB2 receptor still remain to be fully defined even though several reported experimental and clinical data show promising applications in different disease areas. Previ- ous studies have demonstrated that CB2 selective ago- nists are analgesics in different neuropathic and inflammatory pain models, 18–20 which would confer them some potential therapeutic utility in chronic inflammatory diseases such as atherosclerosis. Beneficial effects of CB2 receptor activation in models of neurode- generative disorders, such as Huntington and Alzhei- mer’s diseases, were also reported, leading to a possible neuroprotective role for CB2 ligands. 21–23 Other preclinical studies have highlighted the potential of CB2 ligands in the treatment of cancer by eliciting apoptosis of brain and immune system tumor cells. 24,25 Another potential role of the CB2 receptors could include bone regeneration, as selective CB2 agonists were shown to decrease bone loss in animal studies. 26,27 The particular attractive feature about CB2-selective ligands resides in the distribution of this receptor. CB2 is mainly expressed in immune tissues located in the periphery, with only low levels found in neurons of the central nervous system, minimizing therefore the side effects observed with the CB1-selective ligands. Several classes of CB2 ligands originating from natural and synthetic sources have been reported in the litera- ture. 28–34 Making use of the ever increasing amount of information reported in the literature, along with several hit compounds obtained from a previous screening cam- paign, a cannabinoid program was instigated at our company a few years ago. This program enabled us to develop several classes of CB1/CB2 ligands, like CB2 selective inverse agonists based on a benzimidazole scaf- fold. 35 More recently a different scaffold, based upon a 1,2,3,4-tetrahydropyrrolo[3,4-b]indole moiety, showed good selectivity over CB1 and demonstrated a much dif- 0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2007.09.019 Keywords: Cannabinoids; 1,2,3,4-Tetrahydropyrrolo[3,4-b]indole; CB2 receptor; Agonists. * Corresponding author. Tel.: +1 514 832 3200; fax: +1 514 832 3232; e-mail: daniel.page@astrazeneca.com Available online at www.sciencedirect.com Bioorganic & Medicinal Chemistry Letters 17 (2007) 6183–6187