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.

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Design and Synthesis of Tricyclic Derivatives as High Density Lipoprotein Cholesterol Enhancers. -The synthesis and evaluation of imidazoisoquinolones [cf. (Va), (Vb)], related pyrimidoisoquinolones [cf. (VII)], and imidazonaphthyridines [cf. (Vc)] as high density lipoprotein cholesterol enhancing compounds is described. The synthetic route involves a novel and widely applicable one-step preparation of 3-carboxamidophthalides (III) from 2-acylbenzoic acids (I). -(ELOKDAH, HASSAN; CHAI, SIE-YEARL; HO,