Abstract
A novel series of heteroarylmethoxyphenylalkoxyiminoalkylcarboxylic acids was studied as leukotriene biosynthesis inhibitors. A hypothesis of structure-activity optimization by insertion of an oxime moiety was investigated using REV-5901 as a starting point. A systematic structure-activity optimization showed that the spatial arrangement and stereochemistry of the oxime insertion unit proved to be important for inhibitory activity. The promising lead, S-(E)-11, inhibited LTB(4) biosynthesis in the intact human neutrophil with IC(50) of 8 nM and had superior oral activity in vivo, in a rat pleurisy model (ED(50) = 0.14 mg/kg) and rat anaphylaxis model (ED(50) = 0.13 mg/kg). In a model of lung inflammation, S-(E)-11 blocked LTE(4) biosynthesis (ED(50) of 0.1 mg/kg) and eosinophil influx (ED(50) of 0.2 mg/kg). S-(E)-11 (A-93178) was selected for further preclinical evaluation.
MeSH terms
-
Acrylic Resins
-
Anaphylaxis / drug therapy
-
Animals
-
Anti-Allergic Agents / chemical synthesis
-
Anti-Allergic Agents / chemistry
-
Anti-Allergic Agents / pharmacology
-
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
-
Anti-Inflammatory Agents, Non-Steroidal / chemistry
-
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
-
Ascitic Fluid / metabolism
-
Granuloma / chemically induced
-
Granuloma / drug therapy
-
Humans
-
In Vitro Techniques
-
Leukotriene B4 / antagonists & inhibitors*
-
Leukotriene B4 / biosynthesis
-
Male
-
Mice
-
Neutrophils / drug effects
-
Neutrophils / metabolism
-
Pleuropneumonia / drug therapy
-
Pneumonia / drug therapy
-
Quinolines / chemical synthesis*
-
Quinolines / chemistry
-
Quinolines / pharmacology
-
Rats
-
Stereoisomerism
-
Structure-Activity Relationship
Substances
-
A 93176
-
Acrylic Resins
-
Anti-Allergic Agents
-
Anti-Inflammatory Agents, Non-Steroidal
-
Quinolines
-
Leukotriene B4
-
polyacrylamide