Tiratricol derivative 1a. Eprotirome is a thyroid hormone analog with hypocholesterolemic properties. It binds Thyroid hormone receptor beta. Eprotirome reduces serum LDL cholesterol levels by increasing hepatic clearance due to increased expression of the hepatic LDL-receptor gene, and also reduces the serum level of Lp(a) lipoprotein. This drug was designed to have minimal uptake in nonhepatic tissues thereby avoiding many of the adverse effects associated with thyroid hormone treatment. It is also a lead compound for search of CFTR-inhibitory-factor_Cif inhibitors Compound 1a (KB2115) in Hvorceny et al 2016 (derivative 1a)
The virulence factor cystic fibrosis transmembrane conductance regulator (CFTR) inhibitory factor (Cif) is secreted by Pseudomonas aeruginosa and is the founding member of a distinct class of epoxide hydrolases (EHs) that triggers the catalysis-dependent degradation of the CFTR. We describe here the development of a series of potent and selective Cif inhibitors by structure-based drug design. Initial screening revealed 1a (KB2115), a thyroid hormone analog, as a lead compound with low micromolar potency. Structural requirements for potency were systematically probed, and interactions between Cif and 1a were characterized by X-ray crystallography. On the basis of these data, new compounds were designed to yield additional hydrogen bonding with residues of the Cif active site. From this effort, three compounds were identified that are 10-fold more potent toward Cif than our first-generation inhibitors and have no detectable thyroid hormone-like activity. These inhibitors will be useful tools to study the pathological role of Cif and have the potential for clinical application.