A
hallmark pat
hological feature of t
he Alz
heimer鈥檚 disease (AD) brain is t
he presence of senile plaques, w
hic
h comprise amyloid 尾 (A尾) peptides t
hat are derived from t
he amyloid precursor protein (APP). T
he plaque-containing AD brain is t
houg
ht to be under oxidative stress, as evidenced by increased lipid oxidation products t
hat include isoprostane-F2伪III (iPF2伪III). IPF2伪III can bind to and activate t
he t
hromboxane A2-prostanoid (TP) receptor, and TP receptor activation causes increased A尾 production t
hroug
h en
hancement of APP mRNA stability. Moreover, TP receptor antagonists
have been s
hown to block iPF2伪III-induced increases of A尾 secretion. T
hus, t
he TP receptor may be a potential drug target for AD t
herapy. However,
here we s
how t
hat existing TP receptor antagonists
have poor blood-brain barrier (BBB) permeability, likely due to t
he presence of a carboxylic acid moiety t
hat is believed to be important for receptor interaction, but w
hic
h may
hamper passive diffusion across t
he BBB. We now report selected analogues of a known tetra
hydronap
ht
halene TP receptor antagonist, w
herein t
he carboxylic acid moiety
has been replaced by
heterocyclic bioisosteres. T
hese
heterocyclic analogues retained relatively
hig
h affinity for t
he mouse and
human TP receptors, and, unlike t
he parent carboxylic acid compound, several examples freely diffused across t
he BBB into t
he brain upon administration to mice. T
hese results reveal t
hat brain-penetrant tetra
hydronap
ht
halene TP receptor antagonists can be developed by substituting t
he carboxylic acid moiety wit
h a suitable nonacidic bioisostere. Compounds of t
his type
hold promise as potential lead structures to develop drug candidates for t
he treatment of AD.
<
h4>Keywords:
h4>
hors" href="http://pubs.acs.org/action/doSearch?action=search&searchText=Alzheimer%E2%80%99s+disease&qsSearchArea=searchText">Alzheimer鈥檚 disease; hors" href="http://pubs.acs.org/action/doSearch?action=search&searchText=amyloid+precursor+protein&qsSearchArea=searchText">amyloid precursor protein; hors" href="http://pubs.acs.org/action/doSearch?action=search&searchText=antagonist&qsSearchArea=searchText">antagonist; hors" href="http://pubs.acs.org/action/doSearch?action=search&searchText=blood%5C-brain+barrier&qsSearchArea=searchText">blood-brain barrier; hors" href="http://pubs.acs.org/action/doSearch?action=search&searchText=plaques&qsSearchArea=searchText">plaques; hors" href="http://pubs.acs.org/action/doSearch?action=search&searchText=thromboxane+receptor&qsSearchArea=searchText">thromboxane receptor