SAR studies of acidic dual ¦Ã-secretase/PPAR¦Ã modulators

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• 作者：Martina  ; Hieke^a ;   ; ¹ ; Julia  ; Ness^b ; Ramona  ; Steri^a ; Christine  ; Greiner^c ; Oliver  ; Werz^d ; Manfred  ; Schubert-Zsilavecz^a ; Sascha  ; Weggen^b ;   ; ^{sweggen@uni-duesseldorf.de} ; Heiko  ; Zettl^a ;   ; ¹ ;   ; ^{heiko_zettl@brown.edu}
• 关键词：SAR ; Alzheimer&rsquo ; s disease ; PPAR¦Ã agonists ; ¦Ã-Secretase modulators ; Carboxylic acids
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2011
• 出版时间：15 September 2011
• 年：2011
• 卷：19
• 期：18
• 页码：5372-5382
• 全文大小：908 K

文摘

A novel set of dual ¦Ã-secretase/PPAR¦Ã modulators characterized by a 2-benzyl hexanoic acid scaffold is presented. Synthetic efforts were focused on the variation of the substitution pattern of the central benzene. Finally, we obtained a new class of 2,5-disubstituted 2-benzylidene hexanoic acid derivatives, which act as dual ¦Ã-secretase/PPAR¦Ã modulators in the low micromolar range. We have explored broad SAR and successfully improved the dual pharmacological activity and the selectivity profile against potential off-targets such as NOTCH and COX. Compound mlns="""">17 showed an IC_mlns="""">50 A¦Â42 = 2.4 ¦ÌM and an EC_mlns="""">50 PPAR¦Ã = 7.2 ¦ÌM and could be a valuable tool to further evaluate the concept of dual ¦Ã-secretase/PPAR¦Ã modulators in animal models of Alzheimer¡¯s disease.