Therapeutic potential of urotensin II receptor antagonist in chronic kidney disease and associated comorbidities

Chronic kidney disease (CKD) remains a common disorder with a growing health and economic burden without curative treatment. In diabetic patients, CKD may result from a combination of metabolic and non-metabolic-related factors with mortality mainly driven by cardiovascular events. The marked overactivity of the urotensinergic system in diabetic patients implicates this vasoactive peptide as a possible contributor to the pathogenesis of renal as well as heart failure. Previous preclinical studies with UII antagonists in chronic kidney disease were based on simple endpoints that do not reflect the complex etiology of the disease. The present study was undertaken to extensively characterize 1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino) cyclohexanecarboxylic acid hydrochloride (SAR101099), a potent, selective and orally long-acting UT competitive antagonist inhibiting not only UII but also URP activities. SR101099 treatment more than halved proteinurea and albumin/creatinine ratio in SHR-SP rats fed with salt/fat diet and Dahl-salt-sensitive rats, respectively, and halved albuminuria in a streptozotocin-induced diabetes rat model. Importantly, these effects were accompanied by a decrease in mortality by 50% in SHR-SP and by 35% in the Dahl salt-sensitive rats. SAR101099 was also active on CKD-related cardiovascular pathologies, and partly preserved contractile reserve in models of heart failure induced by myocardial infarction or ischemia/reperfusion in rats and pigs, respectively. SAR101099 exhibited a good safety/tolerability profile at all tested doses in clinical phase-I studies. Finally, these data suggest that optimized patient selection taking into account CKD comorbidities together with new stratification modalities should unveil the therapeutic potential of urotensin antagonists. SIGNIFICANCE STATEMENT: CKD is facing growing health and economic burden, without effective curative treatment available. For years, proper investigations of UT antagonism to treat CKD may have been compromised by the lack of appropriate tools/models to better appreciate its therapeutic value. New potent, selective, orally long-acting cross species UT antagonist such as SAR101099 exerting reno- and cardio-protective effects could offer novel therapeutic opportunities. Its preclinical and clinical results suggest that UT antagonism remains an attractive target in CKD on top of current standard of care.