Chronic kidney disease, cancer, chronic inflammatory disorders, nutritional, and genetic deficiency can cause anemia. Hypoxia causes induction of hypoxia-inducible factor (HIF), which stimulates erythropoietin (EPO) synthesis. Prolyl hydroxylase domain (PHD) enzyme inhibition can stabilize hypoxia-inducible factor (HIF). HIF stabilization also decreases hepcidin, a hormone of hepatic origin, which regulates iron homeostasis. PHD inhibitors represent a novel pharmacological treatment of anemia associated with chronic diseases. Many orally active PHD inhibitors like roxadustat, molidustat, vadadustat, and desidustat are in late phase clinical trials. This review discusses the role of PHD inhibitors in the treatment of anemia associated with chronic diseases.

The nuclear receptor retinoic acid receptor-related orphan receptor gamma (RORγ or RORc) is a key transcription factor for the production of pro-inflammatory cytokines implicated in the pathogenesis of autoimmune diseases. Recently, small molecule inhibitors of RORc drew the enormous attention of the research community worldwide as a possible therapy for autoimmune diseases, mediated by the IL-17 cytokine. With the clinical proof-of-concept inferred from a small molecule inhibitor VTP-43742 for psoriasis and recent inflow of several RORc inhibitors into the clinic for therapeutic interventions in autoimmune diseases, this field continues to evolve. This review briefly summarizes the RORc inhibitors disclosed in the literature and discusses the progress made by these inhibitors in combating autoimmune diseases.

Prolyl hydroxylase (PHD) inhibitors stabilize hypoxia inducible factor (HIF), and exert antianemic effect by potentiating erythropoietin (EPO) expression and down-regulation of hepcidin. ZYAN1 is a novel PHD inhibitor under clinical development for the treatment of anemia. The pharmacodynamic effects of acute and chronic dosing of ZYAN1 were assessed in normal and 5/6 nephrectomized Wistar rats. The effect of ZYAN1 was also investigated in cisplatin-induced anemia using C57 mice. Acute treatment with ZYAN1 increased circulating EPO levels (10.3 ± 3.7 and 40.0 ± 8.5 fold rise at 15 and 30 mg/kg, respectively), reticulocyte count (4.2 ± 0.5 and 6.0 ± 0.2 fold rise at 15 and 30 mg/kg, respectively) and stabilized HIF (28% increase at 45 mg/kg) in normal rats. Nephrectomized rats showed similar dose-related pharmacodynamic effects. In a 28-day study in nephrectomized rats, ZYAN1 administered every alternate day, caused increase in hemoglobin (1.9 ± 0.3 and 2.5 ± 0.4 g/dL) and RBC count (10.7 ± 4.0 and 14.0 ± 4.1%) at 15 and 30 mg/kg respectively. In cisplatin-treated mice also an increase in hemoglobin (3.4 ± 0.2 and 5.9 ± 0.2 g/dL) and RBC count (22.5 ± 2.2 and 37.3 ± 1.7%) at 15 and 30 mg/kg respectively was observed. ZYAN1's effects on hemoglobin and RBC count were distinct from darbepoietin. ZYAN1 demonstrated hematinic potential by combined effects on EPO release and efficient iron utilization. The efficacy of ZYAN1 in disease models of different etiologies suggests that it will be useful in treating wide spectrum of anemia patients.

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A convenient and high-yielding synthesis of unsymmetrical dibenzothiophenes has been achieved by an acid-mediated ring closure of the biphenyl ring having a sulfoxide substituent at the ortho position. Various functional groups are well tolerated in this methodology.

1. ZYAN1 is a prolyl hydroxylase inhibitor in clinical development for treatment of anemia associated with chronic kidney disease (CKD). We evaluated the effect of acute and chronic kidney impairment on the pharmacokinetics of ZYAN1 in rat models. 2. Cisplatin (2.5, 5 and 7.5 mg/kg) was used to induce acute kidney injury (AKI), and five-sixth and total nephrectomy was used to induce chronic kidney injury (CKI) in male Wistar rats. All groups received a single 15 mg/kg oral dose of ZYAN1. Blood/urine samples were analyzed for ZYAN1 to assess peak concentration (C), area under the concentration-time curve (AUC), total body clearance (CL/F) and elimination half-life (T). 3. C and AUC were not significantly different in the various AKI groups or in five-sixth nephrectomized rats, as compared to control rats. Recovery of ZYAN1 in urine was reduced; the impact on the CL/F was minimal. There was a 2-fold increase in AUC with reduction in CL/F in total nephrectomized rats. T was longer for ZYAN1 in the severe AKI/five-sixth nephrectomy rats and total nephrectomy rats as compared to control rats. 4. Based on the rodent data it may be inferred that PK of ZYAN1 in CKD patients may be minimally affected.

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