Alzheimer's disease (AD) brain is characterized by the presence of proteinaceus aggregates comprised of hyperphosphorylated tau proteins and amyloid-� (A�) peptides. Recent studies demonstrated that activation of the thromboxane-prostanoid receptor results in enhanced amyloid precursor protein mRNA stability with increase in A� production and deposition.  These findings indicate that TP receptor antagonists may be therapeutically useful for the treatment of AD. However, most of existing TP receptor antagonists exhibit poor blood-brain barrier permeability, which may be caused by the presence of a carboxylic acid moiety. Hence, we designed, synthesized and evaluated analogues of known TP-receptor antagonists wherein the carboxylic acid moiety was replaced by an isostere or masked as an ester or amide. Evaluation of these compounds for brain penetration and activity in the functional assays resulted in the identification of candidates that can readily access the CNS of mice and antagonize the TP receptor with IC50 values in the nM range.

Design, synthesis, and evaluation of brain-penetrant thromboxane (A<sub>2</sub>) receptor antagonists as potential candidates for Alzheimer's disease

244th National Meeting (2012)

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Design, synthesis, and evaluation of brain-penetrant thromboxane (A2) receptor antagonists as potential candidates for Alzheimer's disease

Design, synthesis, and evaluation of brain-penetrant thromboxane (A₂) receptor antagonists as potential candidates for Alzheimer's disease