Design, Synthesis, and Biological Evaluation of Thio-Containing Compounds with Serum HDL-Cholesterol-Elevating Properties

Abstract

A novel series of substituted sulfanyldihydroimidazolones (1) that modulates high-density lipoprotein cholesterol (HDL-C) has been reported to have HDL-elevating properties in several animal models. Concerns about the chemical and metabolic stability of 1 directed us to explore the structure-activity relationship (SAR) of a related series of substituted thiohydantoins (2). Expansion of the scope of the thiohydantoin series led to exploration of compounds in related thio-containing ring systems 3-7 and the N-cyanoguanidine derivative 8. Compounds were tested sequentially in three animal models to assess their HDL-C elevating efficacy and safety profiles. Further evaluation of selected compounds in a dose-response paradigm culminated in the identification of compound 2.39 as a candidate compound for advanced preclinical studies.

4-Hydroxyisoleucine an unusual amino acid as antidyslipidemic and antihyperglycemic agent

“…The higher TG levels and lower HDL-C increase the risk of coronary heart disease (CHD). 30 The HDL-C mediate the reverse transport of cholesterol from peripheral tissues to the liver for disposal by excretion into bile. This process will disallow the slow accumulation of lipids in artery walls.…”

Synthesis of an azido-tagged low affinity ratiometric calcium sensor

“…3-Azidopropylamine 15 was prepared by the literature method, 37 converted into an isothiocyanate and reacted with the methyl ester of glycine to give thiohydantoin 16 . 38 Knoevenagel condensation 39 with aldehyde 14 completed the fluorophore 17 and saponification of the esters gave NitroAzidoFuraRed.…”

Synthesis and biological evaluation of 3-substituted 5-benzylidene-1-methyl-2-thiohydantoins as potent NADPH oxidase (NOX) inhibitors

“…24 The reactions to synthesize 2-thiohydantoins 11 generally provided good results (more than 90% yield), except in the cases of the cyclohexyl (11a, 66% yield) and 3-chlorophenyl groups (11e, 74% yield), probably due to their electronic and steric effects on the reactivity of nitrogen in isothiocyanate. As a result, the six key intermediates, 11a, 25 11b, 22,26 11c, 27 11d, 28 11e, and 11f 22 were efficiently synthesized.…”