For the purpose of discovering an orally available EP4 subtype-selective agonist, a series of 8-aza prostaglandin E(1) (PGE(1)) analogs were synthesized and evaluated for their affinity for PGE(2) receptor subtypes. Additionally, the structure-activity relationships of these compounds were studied. Among the tested compounds, the 8-aza PGE(1) analog 6 and 8-aza-5-thiaPGE(1) analog 12 had highly potent EP4 receptor affinity, good functional activity, and excellent subtype-selectivity. Furthermore, these analogs demonstrated good stability in human liver microsomes. As a result, we concluded that these two series of 8-aza PGE(1) analogs could be promising chemical leads for an orally available EP4 subtype-selective agonist.

01 Oct 1995·British Journal of Pharmacology

The effect of a synthetic 7‐thiaprostaglandin E₁ derivative, TEI‐6122, on monocyte chemoattractant protein‐1 induced chemotaxis in THP‐1 cells

Article

Author: Endo, Noriaki ; Minoshima, Toru ; Tanaka, Hiroko

The ability of various prostaglandins (PGs) to inhibit monocyte chemotaxis induced by monocyte chemoattractant protein‐1 (MCP‐1) was investigated with a human monocytic leukaemia cell line, THP‐1. Moreover, to investigate the mechanism of the inhibitory action of PGs the involvement of either intracellular adenosine 3″:5″‐cyclic monosphosphate (cyclic AMP) accumulation or intracellular Ca2+ mobilization was studied.

TEI‐6122, a synthetic 7‐thia‐PGE, derivative, inhibited chemotaxis of THP‐1 cells induced by MCP‐1 with an IC50 of 1.5 pM. Its inhibitory activity was 1000 fold more than that of PGE1 and PGE2 (IC50=2.8 nM and 0.9 nM, respectively), which were more potent than other PGs such as PGA1, PGA2, PGF2α and PGI2 (IC50≥1 μm).

With respect to the effect on intracellular cyclic AMP accumulation in THP‐1 cells, TEI‐6122 was as potent as PGEI and PGE2, which were approximately 100 to 1000 fold more potent than the other PGs such as PGA1, PGA2 and PGI2. The minimum concentration of TEI‐6122 required to increase intracellular cyclic AMP accumulation in THP‐1 cells was 1 nM.

TEI‐6122 and PGE1 (4 μm) transiently increased intracellular calcium levels in THP‐1 cells. When added prior to MCP‐1, both PGs partially suppressed the increased in Ca2+ caused by this cytokine. There were no significant differences between the activity of TEI‐6122 and PGEI in either respect.

It is concluded that TEI‐6122, a synthetic 7‐thia‐PGE, derivative is a much more potent inhibitor of MCP‐1‐induced THP‐1 cell chemotaxis than PGEI and PGE2 which are the best inhibitors among the natural PGs tested, while neither intracellular cyclic AMP accumulation nor effects on Ca2+ mobilization account for the extremely potent inhibitory activity of TEI‐6122. Thus, either a novel PGE2 receptor (EP receptor) or a novel intracellular signal transduction system may be involved in the extremely potent chemotaxis inhibitory activity of TEI‐6122.

01 Mar 1995·Prostaglandins

Effect of TFC-612, a 7-thia prostaglandin E1 derivative, on a peripheral arterial occlusive disease model in rats

Article

Author: Motoyama, Y. ; Yoshida, K. ; Seki, J. ; Sakata, Y. ; Dohi, M.

TFC-612, methyl 6-[((1R,2S,3R)-3-hydroxy-2-[(1E,3S,5R)-3-hydroxy-5- methyl-1-nonenyl)-5-oxocyclopentyl]-thio]-hexanoate, inhibited the progression of the lesion in a lauric acid-induced peripheral arterial occlusive model at 1.0 mg/kg p.o. or 1.0 microgram/rat/h s.c. in rats. Aspirin (32 mg/kg, p.o.), an anti-platelet drug, did not suppress the lesion growth. On the other hand, ketanserin (10 mg/kg, p.o.), a 5-HT2 antagonist, also inhibited the progression of the lesion. In vitro, TFC-612 inhibited rat platelet aggregation induced by collagen and ADP with IC50 values of 5.4 ng/mL and 9.5 ng/mL, respectively. Aspirin also inhibited collagen-induced aggregation with an IC50 value of 6.3 micrograms/mL, but not ADP-induced aggregation at 180 micrograms/mL. Ketanserin had no effect on either aggregation at 40 micrograms/mL. In ex vivo experiments, aspirin inhibited platelet aggregation induced by collagen at 10 and 32 mg/kg in rats. However, TFC-612 showed significant inhibition only at 10 mg/kg. TFC-612 and ketanserin increased dermal blood flow in the rat paw at 1.0 microgram/kg i.v. and 100 micrograms/kg i.v., respectively. Aspirin had no effect on blood flow at 3.2 mg/kg i.v. These results suggest that the improvement of microcirculation, in addition to anti-platelet action by TFC-612, contributes to its inhibitory effect in a peripheral arterial occlusive model in rats.

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Indication	Highest Phase	Country/Location	Organization	Date
Thrombosis	Phase 2	-	Teijin Pharma Ltd.	-

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