title: Identification of clinically viable quinolinol inhibitors of botulinum neurotoxin A light chain.
abstract: Botulinum neurotoxins (BoNT) are the most potent toxins known and a significant bioterrorist threat. Few small molecule compounds have been identified that are active in cell-based or animal models, potentially due to toxin enzyme plasticity. Here we screened commercially available quinolinols, as well as synthesized hydroxyquinolines. Seventy-two compounds had IC50 values below 10 μM, with the best compound exhibiting submicromolar inhibition (IC50 = 0.8 μM). Structure-activity relationship trends showed that the enzyme tolerates various substitutions at R1 but has a clear preference for bulky aryl amide groups at R2, while methylation at R3 increased inhibitor potency. Evaluation of the most potent compounds in an ADME panel showed that these compounds possess poor solubility at pH 6.8, but display excellent solubility at low pH, suggesting that oral dosing may be possible. Our data show the potential of quinolinol compounds as BoNT therapeutics due to their good in vitro potencies and favorable ADME properties.
authors.affiliation: Department of Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Dejan
authors.initials: D
authors.lastname: Caglič
authors.forename: Michelle C
authors.initials: MC
authors.lastname: Krutein
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Bompiani
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Barlow
authors.forename: Galit
authors.initials: G
authors.lastname: Benoni
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Pelletier
authors.forename: Allen B
authors.initials: AB
authors.lastname: Reitz
authors.forename: Luke L
authors.initials: LL
authors.lastname: Lairson
authors.forename: Karen L
authors.initials: KL
authors.lastname: Houseknecht
authors.forename: Garry R
authors.initials: GR
authors.lastname: Smith
authors.forename: Tobin J
authors.initials: TJ
authors.lastname: Dickerson
mesh_terms: D000818:Animals; D019274:Botulinum Toxins, Type A / Q000037:antagonists & inhibitors*; D020134:Catalytic Domain; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006912:Hydroxyquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D006912:Hydroxyquinolines; D019274:Botulinum Toxins, Type A