Novel Triazolopyrimidine‐Derived Cannabinoid Receptor 2 Agonists as Potential Treatment for Inflammatory Kidney Diseases

Abstract

The cannabinoid receptor 2 (CB2) system is described to modulate various pathological conditions, including inflammation and fibrosis. A series of new heterocyclic small-molecule CB2 receptor agonists were identified from a high-throughput screen. Lead optimization gave access to novel, highly potent, and selective (over CB1) triazolopyrimidine derivatives. A preliminary structure-activity relationship was established, and physicochemical properties in this compound class were significantly improved toward better solubility, lipophilicity, and microsomal stability. An optimized triazolopyrimidine derivative, (3S)-1-[5-tert-butyl-3-[(1-cyclopropyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol (39), was tested in a kidney ischemia-reperfusion model, in which it showed efficacy at a dose of 10 mg kg(-1) (p.o.). A significant depletion of the three measured kidney markers indicated a protective role of CB2 receptor activation toward inflammatory kidney damage. Compound 39 was also protective in a model of renal fibrosis. Oral treatment with 39 at 3 mg kg(-1) per day significantly decreased the amount of fibrosis by ∼ 40% which was induced by unilateral ureter obstruction.

Selective Cannabinoid 2 Receptor Stimulation Reduces Tubular Epithelial Cell Damage after Renal Ischemia-Reperfusion Injury

“…There was, however, accumulation of SMM-295 in the kidney, which could obviate the rapid decrement of circulating drug and provide more opportunity for renal cell signal activation, particularly during times of renal injury that would negatively impact clearance of exogenous drugs. Consistent with our study, Nettekoven et al (2016) showed that their newly synthesized CB2 receptor agonist could reduce circulating creatinine after renal IRI. Moreover, a partial CB2 agonist, methyl]-5-fluoro-2-pyridinyl]phenyl]methyl]-2,4-imidazolidinedione), was capable of attenuating cisplatin-induced tubular damage by reducing oxidative stress and inflammation in mice (Mukhopadhyay et al, 2016).…”

Celastrol alleviates renal fibrosis by upregulating cannabinoid receptor 2 expression

“…Activation of CB2R reduces inflammation in various inflammatory-associated diseases including nephropathy and cystitis 15 , 17 , and blunts the development of UUO-induced renal fibrosis 20 , 22 . To explore the relationship between celastrol treatment and CB2R function, we measured CB2R expression levels in kidney tissues of mice after UUO surgery.…”

Increased Renal 2-Arachidonoylglycerol Level Is Associated with Improved Renal Function in a Mouse Model of Acute Kidney Injury

“… 20–23 Despite the preponderance of evidence implicating the EC system and ECs in nonrenal IRI, data on the role of ECs in renal IRI remain sparse. 24 , 25 In addition, most of the studies examining the role of the EC system in renal injury focus on the effects of the activation or inhibition of the CB receptors and do not provide data on the tissue level of the endogenous ligands for these receptors, 2-AG and AEA. In this study, we show for the first time that renal IRI leads to a significant increase in renal level of 2-AG, one of the major activators of the EC system.…”