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.
MeSH terms
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Administration, Oral
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Animals
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Cholesterol, HDL / blood*
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Cricetinae
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Drug Design
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Guanidines / chemical synthesis
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Guanidines / chemistry
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Guanidines / pharmacology
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Hypercholesterolemia / blood
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Imidazoles / chemical synthesis*
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Imidazoles / chemistry
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Imidazoles / pharmacology
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Male
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Piperazines / chemical synthesis
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Piperazines / chemistry
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Piperazines / pharmacology
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry
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Pyrimidines / pharmacology
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Rats
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Rats, Sprague-Dawley
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Stimulation, Chemical
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Structure-Activity Relationship
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Thiazolidinediones / chemical synthesis
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Thiazolidinediones / chemistry
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Thiazolidinediones / pharmacology
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Thiohydantoins / chemical synthesis*
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Thiohydantoins / chemistry
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Thiohydantoins / pharmacology
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Thiones / chemical synthesis*
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Thiones / chemistry
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Thiones / pharmacology
Substances
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3-(5-chloro-2-methylphenyl)-1-ethyl-2-thioxoimidazolidin-4-one
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Cholesterol, HDL
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Guanidines
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Imidazoles
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Piperazines
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Pyrimidines
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Thiazolidinediones
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Thiohydantoins
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Thiones
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dicyandiamido