Bioorganic & Medicinal Chemistry 2009-04-15

Botulinum neurotoxin serotype A inhibitors: small-molecule mercaptoacetamide analogs.

Scott T Moe, Andrew B Thompson, Genessa M Smith, Ross A Fredenburg, Ross L Stein, Alan R Jacobson

Index: Bioorg. Med. Chem. 17(8) , 3072-9, (2009)

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Abstract

Botulinum neurotoxin elicits its paralytic activity through a zinc-dependant metalloprotease that cleaves proteins involved in neurotransmitter release. Currently, no drugs are available to reverse the effects of botulinum intoxication. Herein we report the design of a novel series of mercaptoacetamide small-molecule inhibitors active against botulinum neurotoxin serotype A. These analogs show low micromolar inhibitory activity against the isolated enzyme. Structure-activity relationship studies for a series of mercaptoacetamide analogs of 5-amino-3-phenylpyrazole reveal components essential for potent inhibitory activity.