The role of cyclophilin D in interspecies differences in susceptibility to hepatotoxic drug-induced mitochondrial injury.

Test compound A ((5Z)-6-[(2R,3S)-3-({[(4-Chloro-2-methylphenyl)sulfonyl]amino}methyl) bicyclo[2.2.2]oct-2-yl]hex-5-enoic acid) was withdrawn from premarketing clinical trials due to severe liver injury.

Synthesis and evaluation of γ-lactam analogs of PGE₂ as EP4 and EP2/EP4 agonists.

To identify topically effective EP4 agonists and EP2/EP4 dual agonists with excellent subtype selectivity, further optimization of the 16-phenyl ω-chain moiety of the γ-lactam 5-thia prostaglandin E analog and the 2-mercaptothiazole-4-carboxylic acid analog were undertaken. Rat in vivo evaluation of these newly identified compounds as their poly (lactide-co-glycolide) microsphere formulation, from which sustained release of the test compound is possible, led us to discover compounds that showed efficacy in a rat bone fracture healing model after its topical administration without serious influence on blood pressure and heart rate. A structure-activity relationship study is also presented.

Discovery of novel prostaglandin analogs as potent and selective EP2/EP4 dual agonists.

To identify potent EP2/EP4 dual agonists with excellent subtype selectivity, a series of γ-lactam prostaglandin E analogs bearing a 16-phenyl ω-chain were synthesized and evaluated. Structural hybridization of 1 and 2, followed by more detailed chemical modification of the benzoic acid moiety, led us to the discovery of a 2-mercaptothiazole-4-carboxylic acid analog 3 as the optimal compound in the series. An isomer of this compound, the 2-mercaptothiazole-5-carboxylic acid analog 13, showed 34-fold and 13-fold less potent EP2 and EP4 receptor affinities, respectively.

Discovery of a novel EP2/EP4 dual agonist with high subtype-selectivity.

A series of γ-lactam prostaglandin E(1) analogs bearing a 16-phenyl moiety in the ω-chain and aryl moiety in the α-chain were synthesized and biologically evaluated. Among the tested compounds, γ-lactam PGE analog 3 designed as a structural hybrid of 1 and 2 was discovered as the most optimized EP2/EP4 dual agonist with excellent subtype-selectivity (K(i) values: mEP2=9.3 nM, mEP4=0.

Prostaglandin E(2) receptor EP(4)-selective agonist (ONO-4819) increases bone formation by modulating mesenchymal cell differentiation.

Prostaglandin E(2) (PGE(2)) positively regulates bone resorption and formation mainly mediated through the EP(4) receptor, a subtype of PGE(2) receptors. ONO-4819, an EP(4) receptor-selective agonist, has been shown to increase bone volume, density, and strength; however, the mechanism of these effects has yet to be fully elucidated. To explore this matter, ONO-4819 (10μg/kg) was injected into intact rats twice a day for 5weeks, and their bones were then analyzed by morphological techniques.

Roles of thromboxane A(2) and prostacyclin in the development of atherosclerosis in apoE-deficient mice.

Production of thromboxane (TX) A2 and PG I2/prostacyclin (PGI2) is increased in patients with atherosclerosis. However, their roles in atherogenesis have not been critically defined. To examine this issue, we cross-bred atherosclerosis-prone apoE-deficient mice with mice deficient in either the TXA receptor (TP) or the PGI receptor (IP).

Stimulation of bone formation and prevention of bone loss by prostaglandin E EP4 receptor activation.

Bone remodeling, comprising resorption of existing bone and de novo bone formation, is required for the maintenance of a constant bone mass. Prostaglandin (PG)E2 promotes both bone resorption and bone formation. By infusing PGE2 to mice lacking each of four PGE receptor (EP) subtypes, we have identified EP4 as the receptor that mediates bone formation in response to this agent.