ABSTRACT
Prostaglandin D2 (PGD2) acting at the CRTH2 receptor (chemoattractant receptor-homologous molecule expressed on Th2 cells) has been linked with a variety of allergic and other inflammatory diseases. We describe a family of indole-1-sulfonyl-3-acetic acids that are potent and selective CRTH2 antagonists that possess good oral bioavailability. The compounds may serve as novel starting points for the development of treatments of inflammatory disease such as asthma, allergic rhinitis, and atopic dermatitis.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Indoleacetic Acids/chemical synthesis , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Biological Availability , CHO Cells , Calcium/metabolism , Cricetinae , Cricetulus , Humans , Indoleacetic Acids/pharmacokinetics , Indoleacetic Acids/pharmacology , Prostaglandin D2/pharmacology , Rats , Structure-Activity Relationship , Sulfones/chemical synthesis , Sulfones/pharmacokinetics , Sulfones/pharmacologyABSTRACT
Using a furanylthiazole acetic acid as a starting point, a novel series of benzoxazol-5-yl acetic acid derivatives have been identified as heparanase inhibitors. Several compounds possess an IC50 of approximately 200 nM against heparanase, for example, trans 2-[4-[3-(3,4-dichlorophenylamino)-3-oxo-1-propenyl]-2-fluorophenyl]benzoxazol-5-yl acetic acid (16e). Several of the compounds show anti-angiogenic properties. Improvement to the DMPK profile of compounds has provided compounds of potential use in in vivo models.
Subject(s)
Acetates/pharmacology , Benzoxazoles/pharmacology , Enzyme Inhibitors/pharmacology , Glucuronidase/antagonists & inhibitors , Thiazoles/pharmacology , Acetates/chemical synthesis , Acetates/chemistry , Animals , Benzoxazoles/chemical synthesis , Benzoxazoles/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Glucuronidase/blood , Kinetics , Mice , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/chemistryABSTRACT
Chlorination-elimination chemistry coupled with three-component Joullié-Ugi reaction and facile deprotection allowed efficient access to an array of polyhydroxylated pyrrolidines through parallel synthesis that may be considered to be a library of imino (aza) sugars (glycomimetics) and/or dihydroxyprolyl peptides (peptidomimetics). The utility of generating such a library was illustrated by screening against 15 different targets that revealed potent and selective inhibition of the Gaucher's disease glycosyltransferase enzyme glucosylceramide synthase and of primary pathogen model for human hepatitis C virus (HCV) and bovine diarrhoeal virus (BVDV). An observed selectivity for this HCV model over hepatitis B virus and remarkably low toxicity suggest a novel mode of action.
Subject(s)
Antiviral Agents/chemistry , Biomimetic Materials/chemistry , Glycopeptides/chemistry , Pyrrolidines/chemistry , Antiviral Agents/pharmacology , Aza Compounds/chemistry , Aza Compounds/pharmacology , Biomimetic Materials/pharmacology , Carbohydrates/chemistry , Carbohydrates/pharmacology , Diarrhea Viruses, Bovine Viral/drug effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Erythritol/chemistry , Erythritol/pharmacology , Glycopeptides/pharmacology , Glycoside Hydrolases/antagonists & inhibitors , Hepatitis B virus/drug effects , Hydroxyproline/analogs & derivatives , Hydroxyproline/pharmacology , Pyrrolidines/pharmacology , Sugar Alcohols/chemistry , Sugar Alcohols/pharmacologyABSTRACT
A novel class of 2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acids are described as inhibitors of the endo-beta-glucuronidase heparanase. Several of the compounds, for example, 2-[4-propylamino-5-[5-(4-chloro)phenyl-benzoxazol-2-yl]phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid (9c), display potent heparanase inhibitory activity (IC(50) 200-500 nM) and have high selectivity (>100-fold) over human beta-glucuronidase. They also show anti-angiogenic effects. Such compounds should serve as useful biological tools and may provide a basis for the design of novel therapeutic agents.
