ABSTRACT
Estrogen-related receptor α (ERRα) is an orphan nuclear receptor that has been functionally implicated in the regulation of energy homeostasis. Herein is described the development of diaryl ether based thiazolidenediones, which function as selective ligands against this receptor. Series optimization provided several potent analogues that inhibit the recruitment of a coactivator peptide fragment in in vitro biochemical assays (IC(50) < 150 nM) and cellular two-hybrid reporter assays against the ligand binding domain (IC(50) = 1-5 µM). A cocrystal structure of the ligand-binding domain of ERRα with lead compound 29 revealed the presence of a covalent interaction between the protein and ligand, which has been shown to be reversible. In diet-induced murine models of obesity and in an overt diabetic rat model, oral administration of 29 normalized insulin and circulating triglyceride levels, improved insulin sensitivity, and was body weight neutral. This provides the first demonstration of functional activities of an ERRα ligand in metabolic animal models.
Subject(s)
Ethers/chemical synthesis , Hypoglycemic Agents/chemical synthesis , Receptors, Estrogen/metabolism , Thiazolidinediones/chemical synthesis , Administration, Oral , Animals , Binding, Competitive , Biological Availability , Crystallography, X-Ray , Diabetes Mellitus/drug therapy , Dogs , Ethers/pharmacokinetics , Ethers/pharmacology , Female , Humans , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/pharmacology , Insulin/blood , Insulin Resistance , Ligands , Macaca fascicularis , Male , Mice , Mice, Knockout , Models, Molecular , Molecular Structure , Obesity/drug therapy , Rats , Rats, Sprague-Dawley , Receptors, Estrogen/genetics , Structure-Activity Relationship , Thiazolidinediones/pharmacokinetics , Thiazolidinediones/pharmacology , Triglycerides/blood , ERRalpha Estrogen-Related ReceptorABSTRACT
Inhibition of methionine aminopeptidase-2 (MetAP2) represents a novel approach to antiangiogenic therapy. We describe the synthesis and activity of fumagillin analogues that address the pharmacokinetic and safety liabilities of earlier candidates in this compound class. Two-step elaboration of fumagillol with amines yielded a diverse series of carbamates at C6 of the cyclohexane spiroepoxide. The most potent of these compounds exhibited subnanomolar inhibition of cell proliferation in HUVEC and BAEC assays. Although a range of functionalities were tolerated at this position, alpha-trisubstituted amines possessed markedly decreased inhibitory activity, and this could be rationalized by modeling based on the known fumagillin-MetAP2 crystal structure. The lead compound resulting from these studies, (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-enyl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (R)-1-amino-3-methyl-1-oxobutan-2-ylcarbamate, (PPI-2458), demonstrated an improved pharmacokinetic profile relative to the earlier clinical candidate TNP-470, and has advanced into phase I clinical studies in non-Hodgkin's lymphoma and solid cancers.
