ABSTRACT
A high-throughput screen against human DGAT-1 led to the identification of a core structure that was subsequently optimized to afford the potent, selective, and orally bioavailable compound 14. Oral administration at doses ≥0.03 mg/kg significantly reduced postprandial triglycerides in mice following an oral lipid challenge. Further assessment in both acute and chronic safety pharmacology and toxicology studies demonstrated a clean profile up to high plasma levels, thus culminating in the nomination of 14 as clinical candidate ABT-046.
Subject(s)
Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Pyrazoles/chemical synthesis , Pyrimidines/chemical synthesis , Administration, Oral , Animals , Biological Availability , Caco-2 Cells , Databases, Factual , Diacylglycerol O-Acyltransferase/chemistry , Dogs , Female , Ferrets , Gastrointestinal Transit/drug effects , HeLa Cells , Hemodynamics/drug effects , Humans , Hyperlipidemias/blood , Hyperlipidemias/drug therapy , Male , Mice , Mice, Inbred C57BL , Microsomes, Liver/metabolism , Postprandial Period , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Rats , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/chemistry , Structure-Activity Relationship , Triglycerides/blood , Vomiting/chemically inducedABSTRACT
The total synthesis of the marine alkaloid halichlorine is described, based on an approach that involves constructing the fully substituted asymmetric center at an early stage. The five-membered ring is formed by 5-exo-trig radical cyclization and the unsaturated six-membered ring by a process that formally represents a sequential combination of conjugate addition and S(N)2' displacement-a method that is general for making bicyclic compounds with nitrogen at a ring fusion position. A formal synthesis of (+)-halichlorine is also reported, based on the development of a general method for preparing optically pure piperidines. The key step of this method, which was used to make one of our intermediates, is the Claisen rearrangement of a 4-vinyloxy-3,4-dihydro-2H-pyridine-1-carboxylic acid benzyl ester. Such O-vinyl compounds are easily generated in situ from the corresponding alcohols, which are themselves readily assembled from serine and terminal acetylenes.
Subject(s)
Alkaloids/chemical synthesis , Piperidines/chemistry , Spiro Compounds/chemical synthesis , Alkaloids/chemistry , Cyclization , Molecular Conformation , Piperidines/chemical synthesis , Spiro Compounds/chemistry , StereoisomerismABSTRACT
A series of structurally novel and metabolically stable bridged bicyclic carbocycle and heterocycle adamantane replacements have been synthesized and biologically evaluated. Several of these compounds exhibit excellent human and mouse 11beta-HSD1 potency and 11beta-HSD2 selectivity.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Adamantane/chemical synthesis , Adamantane/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , 11-beta-Hydroxysteroid Dehydrogenase Type 2/antagonists & inhibitors , Adamantane/chemistry , Animals , Cell Line , Drug Evaluation, Preclinical , Enzyme Activation/drug effects , Enzyme Inhibitors/chemistry , Humans , In Vitro Techniques , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Molecular Conformation , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of metabolically stable adamantane amide 11beta-HSD1 inhibitors have been synthesized and biologically evaluated. These compounds exhibit excellent HSD1 potency and HSD2 selectivity and good pharmacokinetic and pharmacodynamic profiles.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Adamantane/chemical synthesis , Adamantane/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , 11-beta-Hydroxysteroid Dehydrogenase Type 2/antagonists & inhibitors , Adamantane/chemistry , Animals , Cell Line , Drug Evaluation, Preclinical , Enzyme Activation/drug effects , Enzyme Inhibitors/chemistry , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Humans , In Vitro Techniques , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Molecular Conformation , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of metabolically stable butyrolactam 11beta-HSD1 inhibitors have been synthesized and biologically evaluated. These compounds exhibit excellent HSD1 potency and HSD2 selectivity, pharmacokinetic, and pharmacodynamic profiles.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Lactams/pharmacology , Administration, Oral , Animals , Humans , Lactams/administration & dosage , Lactams/chemical synthesis , Lactams/pharmacokinetics , Metabolic Syndrome/drug therapy , MiceABSTRACT
A convergent synthesis of structurally novel butyrolactam 11beta-HSD1 inhibitors is described. The approach features an efficient Ireland-Claisen reaction to construct a highly substituted aldehyde building block which is converted to a lactam via a tandem reductive amination/cyclization sequence. The generality of the synthetic sequence is demonstrated during the preparation of two additional potent 11beta-HSD1 inhibitors.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Lactams/chemical synthesis , Lactams/pharmacology , Molecular StructureABSTRACT
Boronolide was synthesized stereoselectively from hydroxyacetylfuran 5 and valeraldehyde 6 using a novel dizinc aldol catalyst. Ring closing metathesis provides the lactone ring. The synthesis requires 12 steps and proceeds in 26% overall yield. [reaction: see text]
Subject(s)
Lactones/chemistry , Lactones/chemical synthesis , Plants, Medicinal/chemistry , Medicine, African Traditional , Plant Structures/chemistry , StereoisomerismABSTRACT
[reaction: see text] Syntheses of variously modified ligands for the dinuclear zinc catalysts for the asymmetric aldol and nitroaldol (Henry) reactions are reported. Catalytic enantioselective nitroaldol reactions promoted by these modified ligands led to efficient syntheses of the beta-receptor agonists (-)-denopamine and (-)-arbutamine.
