記述言語：英語   掲載種別：研究論文（学術雑誌）  

A series of 3-(2-aminocarbonyl-4-phenoxymethylphenyl)propanoic acid analogs were synthesized and evaluated for their EP3 antagonist activity in the presence of additive serum albumin. Several compounds were biologically evaluated for their in vivo efficacy with respect to the PGE(2)-induced uterine contraction in pregnant rats as well as their pharmacokinetics. The discovery process of these potent and selective EP3 antagonists and their structure activity relationship are also presented.

DOI： 10.1016/j.bmc.2009.11.023

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A series of acrylic acids and their structurally related compounds were evaluated for their binding affinity to four EP receptor subtypes (EP1-4). Starting from the initial hit 3, which was discovered in our in-house library, compounds 4 and 5 were identified as new chemical leads as candidates for further optimization towards a selective EP3 receptor antagonist. The identification process of these compounds and their pharmacokinetic profiles are presented.

DOI： 10.1016/j.bmc.2009.08.007

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Amyloid-beta peptides (Abeta), generated by proteolysis of the beta-amyloid precursor protein (APP) by beta- and gamma-secretases, play an important role in the pathogenesis of Alzheimer disease (AD). Inflammation is also believed to be integral to the pathogenesis of AD. Here we show that prostaglandin E(2) (PGE(2)), a strong inducer of inflammation, stimulates the production of Abeta in cultured human embryonic kidney (HEK) 293 or human neuroblastoma (SH-SY5Y) cells, both of which express a mutant type of APP. We have demonstrated using subtype-specific agonists that, of the four main subtypes of PGE(2) receptors (EP(1-4)), EP(4) receptors alone or EP(2) and EP(4) receptors together are responsible for this PGE(2)-stimulated production of Abeta in HEK293 or SH-SY5Y cells, respectively. An EP(4) receptor antagonist suppressed the PGE(2)-stimulated production of Abeta in HEK293 cells. This stimulation was accompanied by an increase in cellular cAMP levels, and an analogue of cAMP stimulated the production of Abeta, demonstrating that increases in the cellular level of cAMP are responsible for the PGE(2)-stimulated production of Abeta. Immunoblotting experiments and direct measurement of gamma-secretase activity suggested that PGE(2)-stimulated production of Abeta is mediated by activation ofgamma-secretase but not of beta-secretase. Transgenic mice expressing the mutant type of APP showed lower levels of Abeta in the brain, when they were crossed with mice lacking either EP(2) or EP(4) receptors, suggesting that PGE(2)-mediated activation of EP(2) and EP(4) receptors is involved in the production of Abeta in vivo and in the pathogenesis of AD.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We examined the effects of vasodilatory prostaglandins (prostacyclin and prostaglandin E(2)) and selective agonists for prostanoid EP(2) and EP(4) receptor on the diameters of retinal blood vessels and fundus (retinal/choroidal) blood flow in rats. Male Wistar rats (8- to 10-week-old) were treated with tetrodotoxin (50 microg/kg, i.v.) to eliminate any nerve activity and prevent movement of the eye and infused with a mixture solution of norepinephrine and epinephrine (1:9) to maintain adequate systemic circulation under artificial ventilation. Fundus images were captured with a digital camera that was equipped with the special objective lens for small animals, and the diameters of retinal arterioles and venules were measured on a personal computer. Fundus blood flow was estimated using a laser Doppler flowmetry. Intravenous infusions of prostacyclin and prostaglandin E(2) dilated retinal blood vessels, increased fundus blood flow and decreased systemic blood pressure in a dose-dependent manner. The effects of vasodilatory prostaglandins on retinal arterioles were greater than those on retinal venules. Similarly, a prostanoid EP(2) receptor agonist (ONO-AE1-259-01) dilated retinal blood vessels, and increased fundus blood flow and decreased systemic blood pressure. However, a prostanoid EP(4) receptor agonist (ONO-AE1-329) failed to increase fundus blood flow, despite its comparable depressor response with those to vasodilatory prostaglandins and the prostanoid EP(2) receptor agonist. The responses to forskolin, an activator of adenylyl cyclase, were very similar to those to prostacyclin and the prostanoid EP(2) receptor agonist. These results suggest that prostacyclin and prostaglandin E(2) act as vasodilators in retinal and choroidal circulation, and prostanoid IP and EP(2) receptors play an important role in the regulation of ocular hemodynamics in rats.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Nonsteroidal antiinflammatories are known to suppress incidence and progression of malignancies including colorectal cancers. However, the precise mechanism of this action remains unknown. Using prostaglandin (PG) receptor knockout mice, we have evaluated a role of PGs in tumor-associated angiogenesis and tumor growth, and identified PG receptors involved. Sarcoma-180 cells implanted in wild-type (WT) mice formed a tumor with extensive angiogenesis, which was greatly suppressed by specific inhibitors for cyclooxygenase (COX)-2 but not for COX-1. Angiogenesis in sponge implantation model, which can mimic tumor-stromal angiogenesis, was markedly suppressed in mice lacking EP3 (EP3(-/-)) with reduced expression of vascular endothelial growth factor (VEGF) around the sponge implants. Further, implanted tumor growth (sarcoma-180, Lewis lung carcinoma) was markedly suppressed in EP3(-/-), in which tumor-associated angiogenesis was also reduced. Immunohistochemical analysis revealed that major VEGF-expressing cells in the stroma were CD3/Mac-1 double-negative fibroblasts, and that VEGF-expression in the stroma was markedly reduced in EP3(-/-), compared with WT. Application of an EP3 receptor antagonist inhibited tumor growth and angiogenesis in WT, but not in EP3(-/-). These results demonstrate significance of host stromal PGE(2)-EP3 receptor signaling in tumor development and angiogenesis. An EP3 receptor antagonist may be a candidate of chemopreventive agents effective for malignant tumors.

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