title: Enhancing the Pharmacokinetic Properties of Botulinum Neurotoxin Serotype A Protease Inhibitors Through Rational Design.
abstract: Botulinum neurotoxin (BoNT), the etiological agent that causes the neuroparalytic disease botulism, has become a highly studied drug target in light of the potential abuse of this toxin as a weapon of bioterrorism. In particular, small molecule inhibitors of the light chain metalloprotease of BoNT serotype A have received significant attention and a number of small molecule and biologic inhibitors have been reported. However, all small molecules reported have been identified from either primary screens or medicinal chemistry follow-up studies, and the pharmacokinetic profiles of these compounds have not been addressed. In this study, we have removed the pharmacologic liabilities of one of the best compounds reported to date, 2,4-dichlorocinnamate hydroxamic acid, and in the process, uncovered a related class of benzothiophene hydroxamic acids that are significantly more potent inhibitors of the BoNT/A light chain, while also possessing greatly improved ADME properties, with the best compound showing the most potent inhibition of BoNT/A light chain reported (K(i) = 77 nM). Using a strategy of incorporating traditional drug development filters early into the discovery process, potential liabilities in BoNT/A lead compounds have been illuminated and removed, clearing the path for advancement into further pharmacologic optimization and in vivo efficacy testing.
authors: Department of Chemistry and Worm Institute of Research and Medicine (WIRM), The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Petr
authors: P
authors: Capek
authors: Yan
authors: Y
authors: Zhang
authors: Deborah J
authors: DJ
authors: Barlow
authors: Karen L
authors: KL
authors: Houseknecht
authors: Garry R
authors: GR
authors: Smith
authors: Tobin J
authors: TJ
authors: Dickerson