Brain-Penetrant Tetrahydronaphthalene Thromboxane A2-Prostanoid (TP) Receptor Antagonists as Prototype Therapeutics for Alzheimer’s Disease

Abstract

A hallmark pathological feature of the Alzheimer's disease (AD) brain is the presence of senile plaques, which comprise amyloid β (Aβ) peptides that are derived from the amyloid precursor protein (APP). The plaque-containing AD brain is thought to be under oxidative stress, as evidenced by increased lipid oxidation products that include isoprostane-F2αIII (iPF2αIII). IPF2αIII can bind to and activate the thromboxane A2-prostanoid (TP) receptor, and TP receptor activation causes increased Aβ production through enhancement of APP mRNA stability. Moreover, TP receptor antagonists have been shown to block iPF2αIII-induced increases of Aβ secretion. Thus, the TP receptor may be a potential drug target for AD therapy. However, here we show that existing TP receptor antagonists have poor blood-brain barrier (BBB) permeability, likely due to the presence of a carboxylic acid moiety that is believed to be important for receptor interaction, but which may hamper passive diffusion across the BBB. We now report selected analogues of a known tetrahydronaphthalene TP receptor antagonist, wherein the carboxylic acid moiety has been replaced by heterocyclic bioisosteres. These heterocyclic analogues retained relatively high affinity for the mouse and human TP receptors, and, unlike the parent carboxylic acid compound, several examples freely diffused across the BBB into the brain upon administration to mice. These results reveal that brain-penetrant tetrahydronaphthalene TP receptor antagonists can be developed by substituting the carboxylic acid moiety with a suitable nonacidic bioisostere. Compounds of this type hold promise as potential lead structures to develop drug candidates for the treatment of AD. KEYWORDS: Alzheimer's disease, amyloid precursor protein, antagonist, blood-brain barrier, plaques, thromboxane receptor A lzheimer's disease (AD) is the most common cause of dementia in elderly populations, affecting approximately 10% of individuals over age 65. 1,2 The AD brain is characterized by overt neurodegeneration 3 and the presence of senile plaques comprising insoluble fibrils of Aβ peptides which are produced through sequential proteolytic cleavage of the amyloid precursor protein (APP). 4 A second pathological hallmark of the AD brain is the occurrence of intracellular inclusions composed of hyperphosphorylated tau proteins. 5,6 Familial forms of AD can be caused by mutations in APP that result in increased proteolytic generation of amyloidogenic Aβ peptides, as well as by mutations in the presenilin proteins that are required for the proteolytic processing of APP to yield Aβ. 7−10 These genetic data provide compelling support for the "amyloid" hypothesis, which postulates that it is the production of Aβ that drives disease pathogenesis in AD. Accordingly, there is significant interest in identifying therapeutic strategies that will lead to decreased Aβ production, and there are ongoing efforts to identify inhibitors of the enzymes that generate Aβ. 11,12 A consequence of Aβ plaque deposition in the AD ...

Inflammatory Eicosanoids Increase Amyloid Precursor Protein Expression via Activation of Multiple Neuronal Receptors

“…QBI293 cells stably expressing both the human TP receptor (hTP) and human APP 695 (hTP-hAPP cells) were transfected with control siRNA or siRNA directed to each of the three G-proteins and incubated for 24 h, followed by 48 h treatment in the presence or absence of the TP receptor agonist, [1S-1α,2ß(5Z),3α(1E,3R*),4α)]-7-[-3-(3-hydroxy-4-(4”-iodophenoxy)-1-butenyl)-7-oxabicyclo-[2.2.1]heptan-2-yl]-5-heptenoic acid (IBOP). In agreement with prior studies 11 12 , IBOP caused a 2-3-fold increase in APP mRNA and protein in cells receiving control siRNA relative to non-IBOP treated cells ( Fig. 1 ).…”

“…To investigate the intracellular signaling molecules involved in the previously reported TP receptor-induced increases in APP expression and Aβ production that result from APP mRNA stabilization 11 12 , we utilized siRNA directed to Gα q , Gα 12 , and Gα 13 , the G-protein α-subunits most commonly implicated in TP receptor signal transduction 17 . QBI293 cells stably expressing both the human TP receptor (hTP) and human APP 695 (hTP-hAPP cells) were transfected with control siRNA or siRNA directed to each of the three G-proteins and incubated for 24 h, followed by 48 h treatment in the presence or absence of the TP receptor agonist, [1S-1α,2ß(5Z),3α(1E,3R*),4α)]-7-[-3-(3-hydroxy-4-(4”-iodophenoxy)-1-butenyl)-7-oxabicyclo-[2.2.1]heptan-2-yl]-5-heptenoic acid (IBOP).…”

“…The inflammation observed in AD brain results largely from increased microglial activation in the vicinity of senile plaques 6 7 and a number of glial-derived inflammatory molecules, including cytokines, chemokines and eicosanoids, as well as oxidizing molecules, have been suggested to exacerbate AD neuropathology 5 8 . For example, isoprostane F2αIII (iPF2αIII), a lipid oxidation product thought to be elevated in AD brain 9 10 , can activate the thromboxane A2 (TXA2)-prostanoid (TP) receptor on neurons with a resulting increase of APP mRNA stability that leads to enhanced APP expression and Aβ production 11 12 . Similarly, TXA2 itself may also be increased in AD brain, as this eicosanoid is produced by activated microglia 13 .…”

Brain changes associated with thromboxane receptor antagonist SQ 29,548 treatment in a mouse model

“…Although the concentration of SQ 29,548 used was well below the level that allows significant brain accumulation (Soper et al, ), it was clearly sufficient to have brain effects on PG levels as well as behavioral outcomes. This presumably was due to inhibition of peripheral TP receptors.…”

Therapeutic implications of the prostaglandin pathway in Alzheimer's disease

“…Both molecules are elevated in urine samples from probable AD patients [122, 123], and administration of thromboxane receptor (TP) antagonists Daltroban and S18886 result in a reduction of Aβ. Conversely, TP receptor agonist I-BOP resulted in increased Aβ levels, further demonstrating the therapeutic potential of modulation of individual prostaglandin receptor effectors [124, 125]. Other non-PGE 2 receptors and drugs can be found in Table 2.…”