title: Inhibition of aberrant complement activation by a dimer of acetylsalicylic acid.
abstract: We here report synthesis for the first time of the acetyl salicylic acid dimer 5,5'-methylenebis(2-acetoxybenzoic acid) (DAS). DAS inhibits aberrant complement activation by selectively blocking factor D of the alternative complement pathway and C9 of the membrane attack complex. We have previously identified aurin tricarboxylic and its oligomers as promising agents in this regard. DAS is much more potent, inhibiting erythrocyte hemolysis by complement-activated serum with an IC50 in the 100-170 nanomolar range. There are numerous conditions where self-damage from the complement system has been implicated in the pathology, including such chronic degenerative diseases of aging as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and age-related macular degeneration. Consequently, there is a high priority for the discovery and development of agents that can successfully treat such conditions. DAS holds considerable promise for being such an agent.
authors.affiliation: Kinsmen Laboratory of Neurological Research, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Moonhee
authors.initials: M
authors.lastname: Lee
authors.affiliation: Department of Chemistry, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Matthew
authors.initials: M
authors.lastname: Wathier
authors.affiliation: Department of Chemistry, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Love
authors.affiliation: Kinsmen Laboratory of Neurological Research, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Edith
authors.initials: E
authors.lastname: McGeer
authors.affiliation: Kinsmen Laboratory of Neurological Research, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: mcgeerpl@mail.ubc.ca.
authors.forename: Patrick L
authors.initials: PL
authors.lastname: McGeer
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000209:etiology; D000818:Animals; D001241:Aspirin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D001312:Aurintricarboxylic Acid; D001559:Benzhydryl Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D002415:Cats; D002478:Cells, Cultured; D003167:Complement Activation / Q000187:drug effects*; D003183:Complement C6 / Q000037:antagonists & inhibitors; D011416:Complement Factor D / Q000037:antagonists & inhibitors*; D015938:Complement Membrane Attack Complex; D003170:Complement Pathway, Alternative; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004912:Erythrocytes / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D008268:Macular Degeneration / Q000188:drug therapy / Q000209:etiology; D058990:Molecular Targeted Therapy; D051381:Rats
chemical_list: C000608072:5,5'-methylenebis(2-acetoxybenzoic acid); D001559:Benzhydryl Compounds; D003183:Complement C6; D015938:Complement Membrane Attack Complex; D001312:Aurintricarboxylic Acid; D011416:Complement Factor D; D001241:Aspirin
keywords: Age-related macular degeneration; Alzheimer's disease; C9; Factor B; Factor D; Membrane attack complex; Properdin