ABSTRACT
A series of (3R,4R)-pyrrolidine-3,4-dicarboxylic acid amides was investigated with respect to their factor Xa inhibitory activity, selectivity, pharmacokinetic properties, and ex vivo antithrombotic activity. The clinical candidate from this series, R1663, exhibits excellent selectivity against a panel of serine proteases and good pharmacokinetic properties in rats and monkeys. A Phase I clinical study with R1663 has been finalized.
Subject(s)
Factor Xa Inhibitors , Pyrrolidines/pharmacology , Pyrrolidines/chemistryABSTRACT
Starting from a hit identified by focused screening, 3-aminopyrrolidine factor Xa inhibitors were designed. The binding mode as determined by X-ray structural analysis as well as the pharmacokinetic behaviour of selected compounds is discussed.
Subject(s)
Aminoquinolines/pharmacology , Antithrombin III/pharmacology , Drug Design , Drug Evaluation, Preclinical , Factor Xa/metabolism , Aminoquinolines/chemistry , Aminoquinolines/metabolism , Aminoquinolines/pharmacokinetics , Antithrombin III/chemistry , Antithrombin III/metabolism , Antithrombin III/pharmacokinetics , Crystallography, X-Ray , Factor Xa/chemistry , Humans , Models, Molecular , Molecular ConformationABSTRACT
A series of tetrahydro-cyclopenta[b]indoles modulating the activity of the liver-X-receptor (LXR) were derived from a high throughput screening hit. The potency and selectivity for LXRbeta versus LXRalpha was improved. One compound, administered to wild-type mice modestly increased plasma HDL-cholesterol with no change in plasma triglycerides (TG) and reduced effects on liver TG content compared to T0901317. This novel series of LXR agonists shows promise to improve therapeutic efficacy with reduced potential to increase TG.
Subject(s)
Chemistry, Pharmaceutical/methods , DNA-Binding Proteins/chemistry , Indoles/chemical synthesis , Receptors, Cytoplasmic and Nuclear/chemistry , Animals , Cholesterol, HDL/metabolism , Drug Design , Hydrocarbons, Fluorinated/pharmacology , Indoles/pharmacology , Inhibitory Concentration 50 , Liver X Receptors , Male , Mice , Mice, Inbred C57BL , Models, Chemical , Orphan Nuclear Receptors , Sulfonamides/pharmacology , Transcriptional Activation , Triglycerides/metabolismABSTRACT
Inhibition of glycosidases has great potential in the quest for highly potent and specific drugs to treat diseases such as diabetes, cancer, and viral infections. One of the most effective ways of designing such compounds is by mimicking the transition state. Here we describe the structural, kinetic, and thermodynamic dissection of binding of two glucoimidazole-derived compounds, which are among the most potent glycosidase inhibitors reported to date, with two family 1 beta-glycosidases. Provocatively, while inclusion of the phenethyl moiety improves binding by a factor of 20-80-fold, this does not appear to result from better noncovalent interactions with the enzyme; instead, improved affinity may be derived from significantly better entropic contributions to binding displayed by the phenethyl-substituted imidazole compound.
Subject(s)
Archaeal Proteins/antagonists & inhibitors , Bacterial Proteins/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Glucose/chemistry , Imidazoles/chemistry , Sulfolobus solfataricus/enzymology , Thermotoga maritima/enzymology , beta-Glucosidase/antagonists & inhibitors , Archaeal Proteins/chemistry , Bacterial Proteins/chemistry , Enzyme Inhibitors/therapeutic use , Glucose/analogs & derivatives , Humans , Kinetics , Molecular Structure , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/chemistry , Neoplasms/drug therapy , Neoplasms/enzymology , Protein Binding , Sulfolobus solfataricus/chemistry , Thermodynamics , Thermotoga maritima/chemistry , beta-Glucosidase/chemistryABSTRACT
A series of branched and unbranched anilinohexafluoroisopropanols related to the known sulfonamide T0901317 were prepared and evaluated as activators/modulators of both LXRalpha and LXRbeta. A structure-activity relationship was established and compounds with high potency on both the receptors were identified. Many compounds showed a tendency toward selectivity for LXRbeta versus LXRalpha. Several analogues were evaluated for effects on plasma lipoprotein levels in mice. A few of these significantly raised HDL-cholesterol levels in plasma but showed markedly different effects on liver triglyceride content, suggesting that this series may yield candidates with improved efficacy/safety profiles compared to existing molecules.
