RESUMO
A 5-fluoro-tetrahydrocarbazole serotonin reuptake inhibitor (SRI) building block was combined with a variety of linkers and dopamine D2 receptor ligands in an attempt to identify potent D2 partial agonist/SRI molecules for treatment of schizophrenia. This approach has the potential to treat a broader range of symptoms compared to existing therapies. Selected compounds in this series demonstrate high affinity for both targets and D2 partial agonism in cell-based and in vivo assays.
Assuntos
Carbazóis/química , Agonistas de Dopamina/química , Receptores de Dopamina D2/agonistas , Esquizofrenia/tratamento farmacológico , Inibidores Seletivos de Recaptação de Serotonina/química , Antagonistas do Receptor 5-HT1 de Serotonina , Animais , Carbazóis/síntese química , Carbazóis/farmacologia , Modelos Animais de Doenças , Agonistas de Dopamina/síntese química , Agonistas de Dopamina/farmacologia , Ratos , Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Dopamina D2/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Inibidores Seletivos de Recaptação de Serotonina/farmacologiaRESUMO
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.