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

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.

Slowly Signaling G Protein–Biased CB2Cannabinoid Receptor Agonist LY2828360 Suppresses Neuropathic Pain with Sustained Efficacy and Attenuates Morphine Tolerance and Dependence

“…Paclitaxel (Tecoland Corporation, Irvine, CA) was dissolved in a cremophor-based vehicle made of Cremophor EL (Sigma-Aldrich, St. Louis, MO), ethanol (Sigma-Aldrich), and 0.9% saline (Aqualite System; Hospira, Inc., Lake Forest, IL) at a ratio of 1:1:18 as previously published (Deng et al, 2015). LY2828360 (8-(2-chlorophenyl)-2-methyl-6-(4-methylpiperazin-1-yl)-9-(tetrahydro-2H-pyran-4-yl)-9Hpurine) was obtained from Eli Lilly and company (Indianapolis, IN) and synthesized by Eli Lilly (Indianapolis, IN) as previously described (Hollinshead et al, 2013). Morphine (Sigma-Aldrich), or LY2828360, was dissolved in a vehicle containing a 2:1:1:18 ratio of dimethylsulfoxide (DMSO) (Sigma-Aldrich), ALKAMULS EL-620 (Rhodia, Cranbury, NJ), ethanol, and saline.…”

“…LY2828360 (Fig. 1) is a potent CB 2 receptor agonist with similar affinity for human and rat CB 2 receptors (Hollinshead et al, 2013). In a human CB 2 functional assay, approximately 87% maximal stimulation of CB 2 was observed at 20 nM concentrations, whereas only 15% maximal stimulation of CB 1 was observed at 100 mM concentrations (Hollinshead et al, 2013).…”

“…1) is a potent CB 2 receptor agonist with similar affinity for human and rat CB 2 receptors (Hollinshead et al, 2013). In a human CB 2 functional assay, approximately 87% maximal stimulation of CB 2 was observed at 20 nM concentrations, whereas only 15% maximal stimulation of CB 1 was observed at 100 mM concentrations (Hollinshead et al, 2013). LY2828360 showed good CNS penetration and potent oral activity in a preclinical model of joint pain induced by intra-articular monoiodoacetic acid (Hollinshead et al, 2013).…”

“…In the monoiodoacetic acid model, LY2828360 (0.3 mg/kg p.o.) produced a dose-related reversal of pain using incapacitance testing, demonstrating equivalent efficacy to the nonsteroidal anti-inflammatory drug diclofenac (Hollinshead et al, 2013). No specific risks or discomforts associated with LY2828360 were observed in patients with osteoarthritic pain who have taken LY2828360 up to a dose of 80 mg for 4 weeks (Pereira et al, 2013) (www.clinicaltrials.gov identifier: NCT01319929).…”

Development of novel oxazolo[5,4-d]pyrimidines as competitive CB2 neutral antagonists based on scaffold hopping

“…Moreover, Eli Lilly and Co. disclosed a series of purines as selective CB2 agonists [28][29][30][31]. Of note, compound 2 (LY2828360, Figure 1), derived from the lead compound 3 (Figure 1), has been recognized as a potent and efficacious analgesic agent in a rat model of osteoarthritis related chronic pain at a 1 mg/kg oral dose [30]. Accordingly, clinical trials for the treatment of osteoarthritic knee pain were performed [32].…”