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.
Subject(s)
Cholesterol, HDL/blood , Imidazoles/chemical synthesis , Thiohydantoins/chemical synthesis , Thiones/chemical synthesis , Administration, Oral , Animals , Cricetinae , Drug Design , Guanidines/chemical synthesis , Guanidines/chemistry , Guanidines/pharmacology , Hypercholesterolemia/blood , Imidazoles/chemistry , Imidazoles/pharmacology , Male , Piperazines/chemical synthesis , Piperazines/chemistry , Piperazines/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Pyrimidines/pharmacology , Rats , Rats, Sprague-Dawley , Stimulation, Chemical , Structure-Activity Relationship , Thiazolidinediones/chemical synthesis , Thiazolidinediones/chemistry , Thiazolidinediones/pharmacology , Thiohydantoins/chemistry , Thiohydantoins/pharmacology , Thiones/chemistry , Thiones/pharmacologyABSTRACT
Three novel metabolites of the angiotensin-II (A-II) receptor antagonist tasosartan have been identified in humans, and the syntheses and pharmacologic profiling of these metabolites are reported. Each metabolite bound the human A-II receptor with IC(50)s between 20 and 45nM. The in vivo effects of these compounds in attenuating the pressor response to angiotensin-II challenge in anesthetized rats were also investigated. An unsaturated diol metabolite exhibited in vivo efficacy at intravenous doses of 1 and 3mg/kg, while the other metabolites, both carboxylic acids, had no significant effect at the same doses.
