Substituted 2-phenyl-benzimidazole derivatives: novel compounds that suppress key markers of allergy.
The pharmacotherapy of allergy and asthma has traditionally focused on the effecter molecules of the allergic cascade, while neglecting targets that play an early role in their development. Reasoning that IgE is central to the expansion of atopic diseases, we identified and extended a novel family of 2-(substituted phenyl)-benzimidazole inhibitors of IgE response. Pharmacological activity depends on an intact phenylbenzimidazole-bis-amide backbone, and is optimized by the presence of lipophilic terminal groups composed of either bis cycloalkyl or combinations of aliphatic and halogen-substituted aromatic groups. These compounds also inhibit IL-4 and IL-5 responses in T cells and CD23 expression on B cells, with potencies that parallel their inhibition of IgE. The broad profile of these compounds thus underscores their potential for treating the multifarious pathology of asthma.
Richards
Mark L
ML
Avanir Pharmaceuticals, 11388 Sorrento Valley Road, San Diego, CA 92121, USA. mrichards@avanir.com
Lio
Shirley Cruz
SC
Sinha
Anjana
A
Banie
Homayon
H
Thomas
Richard J
RJ
Major
Michael
M
Tanji
Mark
M
Sircar
Jagadish C
JC
D000284:Administration, Oral; D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001682:Biological Availability; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006967:Hypersensitivity / Q000188:drug therapy*; D007073:Immunoglobulin E / Q000097:blood; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008807:Mice, Inbred BALB C; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
D001562:Benzimidazoles; D016207:Cytokines; D007073:Immunoglobulin E; C117755:2-phenylbenzimidazole