Liver X Receptors (LXRs) are members of the nuclear receptor family, and they play significant role in lipid and cholesterol metabolism. Moreover, they are key regulators of several inflammatory pathways. Pharmacological modulation of LXRs holds great potential in treatment of metabolic diseases, neurodegenerative diseases, and cancer. We were the first group to identify LXR inverse agonists SR9238 (6) and SR9243 (7) and demonstrate their potential utility in treating liver diseases and cancer. Here, we present the results of structure-activity relationship (SAR) studies, based around SR9238 (6) and SR9243 (7). This study led to identification of 16, 17, 19, and 38, which were more potent inverse agonists than SR9238 (6) and SR9243 (7) and inhibited expression of the fatty acid synthase gene in DU145 cells. We previously demonstrated that inhibition of FASN is correlated to the anticancer activity of SR9243 (7) and this suggests that new inverse agonists have great potential as anticancer agents. We identified compounds with distinct selectivity toward both LXR isoforms, which can be excellent tools to study the pharmacology of both isoforms. We employed molecular dynamic (MD) simulations to better understand the molecular mechanism underlying inverse agonist activity and to guide our future design.
Heterocyclic Compounds, 4 or More Rings/pharmacology , Liver X Receptors/agonists , Sulfonamides/pharmacology , Dose-Response Relationship, Drug , HEK293 Cells , Heterocyclic Compounds, 4 or More Rings/chemistry , Humans , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Sulfonamides/chemistry
We describe the structure-based design, synthesis, and enzymatic activity of a series of substituted pyrazinones as inhibitors of the TF/VIIa complex. These inhibitors contain substituents meta to the P(1) amidine designed to explore additional interactions with the VIIa residues in the so-called 'S(1) side pocket'. A crystal structure of the designed inhibitors demonstrates the ability of the P(1) side pocket moiety to engage Lys192 and main chain of Gly216 via hydrogen bond interactions, thus, providing additional possibility for chemical modification to improve selectivity and/or physical properties of inhibitors.
Benzamidines/chemistry , Drug Design , Factor VIIa/antagonists & inhibitors , Fibrinolytic Agents/chemical synthesis , Pyrazines/chemical synthesis , Serine Proteinase Inhibitors/chemical synthesis , Binding Sites , Factor VIIa/chemistry , Fibrinolytic Agents/chemistry , Fibrinolytic Agents/pharmacology , Inhibitory Concentration 50 , Models, Molecular , Protein Binding , Pyrazines/chemistry , Pyrazines/pharmacology , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Structure-Activity Relationship
[reaction: see text] A general demonstration of orthogonal selectivity of the Liebeskind-Srogl cross-coupling protocol compared to the Suzuki-Miyaura and Stille variants is reported.
