Orally active, species-independent novel A3 adenosine receptor antagonist protects against kidney injury in db/db mice

Abstract

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease, and the current pharmacological treatment for DKD is limited to renin-angiotensin system (RAS) inhibitors. Adenosine is detectable in the kidney and is significantly elevated in response to cellular damage. While all 4 known subtypes of adenosine receptors, namely, A1AR, A2aAR, A2bAR, and A3AR, are expressed in the kidney, our previous study has demonstrated that a novel, orally active, species-independent, and selective A3AR antagonist, LJ-1888, ameliorates unilateral ureteral obstruction-induced tubulointerstitial fibrosis. The present study examined the protective effects of LJ-2698, which has higher affinity and selectivity for A3AR than LJ-1888, on DKD. In experiment I, dose-dependent effects of LJ-2698 were examined by orally administering 1.5, 5, or 10 mg/kg for 12 weeks to 8-week-old db/db mice. In experiment II, the effects of LJ-2698 (10 mg/kg) were compared to those of losartan (1.5 mg/kg), which is a standard treatment for patients with DKD. LJ-2698 effectively prevented kidney injuries such as albuminuria, glomerular hypertrophy, tubular injury, podocyte injury, fibrosis, inflammation, and oxidative stress in diabetic mice as much as losartan. In addition, inhibition of lipid accumulation along with increases in PGC1α, a master regulator of mitochondrial biogenesis, were demonstrated in diabetic mice treated with either LJ-2698 or losartan. These results suggest that LJ-2698, a selective A3AR antagonist, may become a novel therapeutic agent against DKD.

Blockade of the Adenosine A3 Receptor Attenuates Caspase 1 Activation in Renal Tubule Epithelial Cells and Decreases Interleukins IL-1β and IL-18 in Diabetic Rats

“…It was previously demonstrated that the use of ADORA3 antagonists have anti-inflammatory effects [38], however the renoprotective properties of the use of these antagonists in diabetic nephropathy has been suggested, but not mechanistically understood [40]. Our first approach was to evaluate the physiological effects of the ADORA3 antagonists administered to rats following one month from induction of experimental diabetes for a period of four weeks.…”

Focusing on Adenosine Receptors as a Potential Targeted Therapy in Human Diseases

“…Anti-inflammation Diabetic kidney diseases LJ-2698 [195] Atherosclerosis and hyperlipidemia LJ-1888 [196] Ischemia Protection Angina IB-MECA [197] CI-IB-MECA [198] CP-532,903 [199] Adaptation Hypertrophy Angiogenesis…”

“…The latest study shows that LJ-1888, a selective antagonist for A 3 AR, is a feasible novel candidate for the treatment of atherosclerosis and hypercholesterolemia [196]. Moreover, LJ-2698, a highly selective and species-independent A 3 AR antagonist, ameliorated diabetic kidney complications [195].…”

Structure activity relationship of 2-arylalkynyl-adenine derivatives as human A3 adenosine receptor antagonists

“…Selective A 3 AR antagonists have potential utility in glaucoma, kidney protection, inflammatory conditions and cancer. 38,39 Some of the adenine derivatives show clear selectivity for the hA 3 AR, but none are balanced between A 1 and A 3 ARs. Furthermore, they are not useful as pharmacological probes of the mouse (m) A 3 AR.…”

“…To a solution of 6-chloro-2-iodopurine (30 mg, 0.107 mmol) and N,N-dicyclopropylmethylamine hydrochloride (79 mg, 0.535 mmol) in isopropanol (2 mL) was added diisopropylethylamine (0.2 mL, 138 mg, 1.07 mmol) at room temperature, and the reaction mixture was heated at 90°C in a microwave synthesizer for 3 h. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with water (5 mL × 2). After all volatiles were evaporated under reduced pressure, the crude was purified by silica gel column chromatography (dichloromethane : methanol = 50 : 1) to afford compound 38 (37 mg, 97%) as a white solid; 1 N-Cyclopentyl-2-iodo-9H-purin-6-amine (39). To a solution of 6-chloro-2-iodopurine (24 mg, 86 μmol) and cyclopentylamine (12 μL, 11 mg, 0.128 mmol) in ethanol was added triethylamine (13 mg, 18 μL, 0.128 mmol) at room temperature, and the reaction mixture was refluxed for 15 h. After all volatiles were evaporated under reduced pressure, the crude was purified by silica gel column chromatography (dichloromethane : methanol = 50 : 1) to afford compound 39 (14 mg, 48%) as a white solid; 1…”