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.

A series of chromane-2-carboxylic acid derivatives was synthesized and evaluated for PPAR agonist activities. A structure-activity relationship was developed toward PPARalpha/gamma dual agonism. As a result, (2R)-7-(3-[2-chloro-4-(4-fluorophenoxy)phenoxy]propoxy)-2-ethylchromane-2-carboxylic acid (48) was identified as a potent, structurally novel, selective PPARalpha/gamma dual agonist. Compound 48 exhibited substantial antihyperglycemic and hypolipidemic activities when orally administered in three different animal models: the db/db mouse type 2 diabetes model, a Syrian hamster lipid model, and a dog lipid model.

Alkylation of 1 -1ithio trisubstituted glycals obtained via the corresponding I-tributylstannyl derivatives constitutes a novel entry into C-glycosides.$ All new compounds were characterized by spectroscopic and/or microanalytical data. Yields refer to chromatographically pure products. Optical rotations were measured in chloroform.

Identification of selective ion channel inhibitors represents a critical step for understanding the physiological role that these proteins play in native systems. In particular, voltage-gated potassium (K V 2) channels are widely expressed in tissues such as central nervous system, pancreas, and smooth muscle, but their particular contributions to cell function are not well understood. Although potent and selective peptide inhibitors of K V 2 channels have been characterized, selective small molecule K V 2 inhibitors have not been reported. For this purpose, highthroughput automated electrophysiology (IonWorks Quattro; Molecular Devices, Sunnyvale, CA) was used to screen a 200,000-compound mixture (10 compounds per sample) library for inhibitors of K V 2.1 channels. After deconvolution of 190 active samples, two compounds (A1 and B1) were identified that potently inhibit K V 2.1 and the other member of the K V 2 family, K V 2.2 (IC 50 , 0.1-0.2 ⌴), and that possess good selectivity over K V 1.2 (IC 50 Ͼ10 ⌴). Modeling studies suggest that these compounds possess a similar three-dimensional conformation. Compounds A1 and B1 are Ͼ10-fold selective over Na V channels and other K V channels and display weak activity (5-9 ⌴) on Ca V channels. The biological activity of compound A1 on native K V 2 channels was confirmed in electrophysiological recordings of rat insulinoma cells, which are known to express K V 2 channels. Medicinal chemistry efforts revealed a defined structure-activity relationship and led to the identification of two compounds (RY785 and RY796) without significant Ca V channel activity. Taken together, these newly identified channel inhibitors represent important tools for the study of K V 2 channels in biological systems.