ABSTRACT
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.
Subject(s)
Carbazoles/chemistry , Dopamine Agonists/chemistry , Receptors, Dopamine D2/agonists , Schizophrenia/drug therapy , Selective Serotonin Reuptake Inhibitors/chemistry , Serotonin 5-HT1 Receptor Antagonists , Animals , Carbazoles/chemical synthesis , Carbazoles/pharmacology , Disease Models, Animal , Dopamine Agonists/chemical synthesis , Dopamine Agonists/pharmacology , Rats , Receptor, Serotonin, 5-HT1A/metabolism , Receptors, Dopamine D2/metabolism , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/pharmacologyABSTRACT
1-Aminoethyl-3-arylsulfonyl-1H-indoles 1 are 5-HT(6) receptor ligands with modest activity in a 5-HT(6) cyclase assay. Introduction of an additional nitrogen in the indole ring provides 1-aminoethyl-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines 2 with both enhanced 5-HT(6) affinity and cyclase activity, many acting as 5-HT(6) agonists. We constrained the basic side chain as part of a ring to make 1-(azacyclyl)-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines incorporating a pyrrolidinyl 3 or piperidinyl 4 ring system. Preparation of compounds 3 and 4 required synthesis of the key intermediates, 1-(pyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyridines 7 and 1-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridines 8, respectively. Intermediates 7 were prepared through alkylation of 7-azaindole while the intermediates 8 required an alternate synthesis. The compounds of both series 3 and 4 were shown to have high binding affinities for the 5-HT(6) receptor. The in vitro functional activity at the 5-HT(6) receptor varied depending on various functionalities including the selection of the arylsulfonyl, the substitution on the arylsulfonyl group, the ring size, and the substitution on the basic amine moiety producing either 5-HT(6) receptor agonists or antagonists.
Subject(s)
Pyridines/pharmacology , Receptors, Serotonin/chemistry , Serotonin Antagonists/pharmacology , Serotonin Receptor Agonists/pharmacology , Binding, Competitive , HeLa Cells/drug effects , Humans , Ligands , Molecular Structure , Pyridines/chemical synthesis , Pyridines/chemistry , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/chemistry , Serotonin Receptor Agonists/chemical synthesis , Serotonin Receptor Agonists/chemistry , Structure-Activity RelationshipABSTRACT
Indole oxoacetic acid derivatives were prepared and evaluated for in vitro binding to and inactivation of human plasminogen activator inhibitor-1 (PAI-1). SAR based on biochemical, physiological, and pharmacokinetic attributes led to identification of tiplaxtinin as the optimal selective PAI-1 inhibitor. Tiplaxtinin exhibited in vivo oral efficacy in two different models of acute arterial thrombosis. The remarkable preclinical safety and metabolic stability profiles of tiplaxtinin led to advancing the compound to clinical trials.
Subject(s)
Indoles/chemical synthesis , Plasminogen Activator Inhibitor 1/metabolism , Serine Proteinase Inhibitors/chemical synthesis , Administration, Oral , Animals , Biological Availability , Carotid Artery Thrombosis/drug therapy , Coronary Thrombosis/drug therapy , Dogs , Drug Design , Drug Evaluation, Preclinical , Humans , Indoleacetic Acids , Indoles/chemistry , Indoles/pharmacology , Rats , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
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.
