lu-302872 and Fibrosis

The endothelin axis and in particular the two endothelin receptors, ETA and ETB, are targets for therapeutic intervention in human diseases. Endothelin-receptor antagonists are in clinical use to treat pulmonary arterial hypertension and have been under clinical investigation for the treatment of several other diseases, such as systemic hypertension, cancer, vasospasm, and fibrogenic diseases. In this Perspective, we review the molecules that have been evaluated in human clinical trials for the treatment of pulmonary arterial hypertension, as well as other cardiovascular diseases, cancer, and fibrosis. We will also discuss the therapeutic consequences of receptor selectivity with regard to ETA-selective, ETB-selective, or dual ETA/ETB antagonists. We will also consider which chemical characteristics are relevant to clinical use and the properties of molecules necessary for efficacy in treating diseases against which known molecules displayed suboptimal efficacy.

Topics: Animals; Cardiovascular Diseases; Clinical Trials as Topic; Endothelin Receptor Antagonists; Fibrosis; Humans; Hypertension, Pulmonary; Neoplasms; Receptors, Endothelin

Tissue concentrations of ET-1 are markedly elevated in the kidneys of Han:Sprague-Dawley (Han:SPRD) rats, a model of human autosomal dominant polycystic kidney disease (ADPKD). This study analyzed whether disease progression might be attenuated by endothelin receptor antagonists. Heterozygous Han:SPRD rats received an ETA receptor antagonist (LU 135252), a combined ETA/ETB receptor antagonist (LU 224332), or placebo for 4 mo. Glomerulosclerosis, protein excretion, and GFR remained unchanged, whereas interstitial fibrosis was enhanced by both compounds. BP was not reduced by both compounds in Han:SPRD rats. Renal blood flow (RBF) decreased in ADPKD rats treated with the ETA receptor antagonist. Long-term ETA receptor blockade furthermore increased markedly the number of renal cysts (ADPKD rats, 390 +/- 119 [cysts/kidney section +/- SD]; LU 135252-treated APKD rats, 1084 +/- 314; P < 0.001), cyst surface area (ADPKD rats, 7.97 +/- 2.04 [% of total section surface +/- SD]; LU 135252-treated ADPKD rats, 33.83 +/- 10.03; P < 0.001), and cell proliferation of tubular cells (ADPKD rats, 42.2 +/- 17.3 [BrdU-positive cells/1000 cells]; LU 135252-treated ADPKD rats, 339.4 +/- 286.9; P < 0.001). The additional blockade of the ETB receptor attenuated these effects in Han:SPRD rats. Both endothelin receptor antagonists had no effect on BP, protein excretion, GFR, and kidney morphology in Sprague-Dawley rats without renal cysts. It is concluded that ETA receptor blockade enhances tubular cell proliferation, cyst number, and size and reduces RBF in Han:SPRD rats. This is of major clinical impact because endothelin receptor antagonists are upcoming clinically used drugs.

Topics: Animals; Disease Progression; Endothelin Receptor Antagonists; Fibrosis; Kidney; Kidney Tubules; Male; Organ Size; Phenylpropionates; Polycystic Kidney Diseases; Propionates; Pyrimidines; Rats; Rats, Inbred Strains; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Renal Circulation