Substituted pyrazolones require N2 hydrogen bond donating ability to protect against cytotoxicity from protein aggregation of mutant superoxide dismutase 1

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:22

Article

Trippier, Paul C.¹  Benmohammed, Radhia²  Kirsch, Donald R.²  Silverman, Richard B.^1,3 

[1] Northwestern Univ, Dept Chem, Evanston, IL 60208 USA

[2] Cambria Pharmaceut, Cambridge, MA USA

[3] Northwestern Univ, Ctr Mol Innovat & Drug Discovery, Chem Life Proc Inst, Dept Mol Biosci, Evanston, IL 60208 USA

关键词: Amyotrophic lateral sclerosis;    Superoxide dismutase 1;    Neuroprotection;    Pyrazolone;    Pharmacophore;   

DOI  :  10.1016/j.bmcl.2012.08.114

来源: Elsevier

【 摘 要 】

Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal neurodegenerative disease. Although the cause remains unknown, misfolded protein aggregates are seen in neurons of sporadic ALS patients, and familial ALS mutations, including mutations in superoxide dismutase 1 (SOD1), produce proteins with an increased propensity to misfold and aggregate. A structure activity relationship of a lead scaffold exhibiting neuroprotective activity in a G93A-SOD1 mouse model for ALS has been further investigated in a model PC12 cellular assay. Synthesis of biotinylated probes at the N-1 nitrogen of the pyrazolone ring gave compounds (5d-e) that retained activity within 10-fold of the proton-bearing lead compound (5a) and were equipotent with a sterically less cumbersome N-1-methyl substituted analogue (5b). However, when methyl substitution was introduced at N-1 and N-2 of the pyrazolone ring, the compound was inactive (5c). These data led us to investigate further the pharmacophoric nature of the pyrazolone unit. A range of N-1 substitutions were tolerated, leading to the identification of an N-1-benzyl substituted pyrazolone (5m), equipotent with 5a. Substitution at N-2 or excision of N-2, however, removed all activity. Therefore, the hydrogen bond donating ability of the N-2-H of the pyrazolone ring appears to be a critical part of the structure, which will influence further analogue synthesis. (C) 2012 Elsevier Ltd. All rights reserved.

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