15-keto treprostinil

15-keto Treprostinil is an impurity found in treprostinil , which is a stable analog of prostaglandin I2 with a longer plasma half-life. Formulations containing treprostinil are used for the treatment of primary pulmonary hypertension.

8-iso-13,14-dihydro-15-keto Prostaglandin F2α (8-iso-13,14-dihydro-15-keto PGF2α) is a metabolite of the isoprostane, 8-isoprostane (8-iso PGF2α), in rabbits, monkeys and humans. 8-iso PGF2α is a PG-like product of non-specific lipid peroxidation. In both humans and monkeys, exogenously infused 8-isoprostane is converted primarily to metabolites having 2 or 4 carbon atoms removed from the top side chain by β-oxidation. A similar pattern is observed when tritiated 8-isoprostane is infused into rabbits. Early in the infusion (within 10 minutes) 8-iso-13,14-dihydro-15-keto PGF2α was a significant component of the metabolite profile, which was comprised mostly of dinor 8-isoprostane metabolites. 8-iso-13,14-dihydro-15-keto PGF2α weakly inhibits the U-46619 or collagen-induced aggregation of human platelets, although a number of the E-series isoprostanes are much more potent in this assay.

13,14-dihydro-15-keto Prostaglandin E1 inhibits ADP-induced platelet aggregation in human isolated platelet-rich plasma (IC50=14.8 μg/mL) and is a PGE1 metabolite.

15-keto Prostaglandin F2α is a metabolite of Prostaglandin F2α that lowers intraocular pressure in rabbits.

Bimatoprost is the Allergan trade name for 17-phenyl trinor prostaglandin F2α ethyl amide (17-phenyl trinor PGF2α ethyl amide), an F-series PG analog which has been approved for use as an ocular hypotensive drug. Oxidation of the C-15 hydroxyl group produces 15-keto-17-phenyl trinor PGF2α ethyl amide. 15-keto-17-phenyl trinor PGF2α ethyl amide is a potential metabolite of 17-phenyl trinor PGF2α ethyl amide when 17-phenyl trinor PGF2α ethyl amide is administered to intact animals. No pharmacological studies on 15-keto-17-phenyl trinor PGF2α ethyl amide have been reported.

15-keto PGF1α is the initial metabolite of PGF1α via 15-hydroxy PGDH. In mammals, oxidation of C-15 markedly attenuates receptor binding and activity. In fish, the 15-keto compounds serve as post-ovulatory pheromones and are more active than the parent prostaglandins.

15-keto-Prostaglandin E2, an endogenous metabolite, inhibits STAT3 activation through binding to Cys259 and regulates breast cancer cell growth and progression. Additionally, it binds and stabilizes the EP2 and EP4 receptors, activates PPAR-γ, and promotes fungal growth [1] [2] [3].

8-iso-15-keto Prostaglandin F2α (8-iso-15-keto PGF2α) is a metabolite of the isoprostane 8-iso PGF2α in rabbits, monkeys, and humans. 8-iso PGF2α is a prostaglandin-like product of non-specific lipid peroxidation. In humans and monkeys, exogenously infused 8-iso PGF2α is converted to metabolites with 2 or 4 carbon atoms removed from the top side chain by β-oxidation, with a similar pattern observed in tritiated 8-iso PGF2α-infused rabbits. Early in the infusion (within 1-2 minutes), 8-iso-15-keto PGF2α is a major component of the metabolite profile, primarily comprising unmetabolized 8-iso PGF2α. 8-iso-15-keto PGF2α is a vasoconstrictor when tested on the rat isolated thoracic aorta, acting via the TP (thromboxane) receptor.

15-keto Latanoprost is a potential metabolite of latanoprost when administered to animals and is a common minor impurity in commercial preparations of the bulk drug compound. Although much less potent than latanoprost, 15-keto Latanoprost can still produce a small but measurable decrease (1 mm Hg) in intraocular pressure in normal cynomolgus monkeys at a dose of 1 μg eye. It also acts as a miotic in normal cats, causing an 8 mm Hg reduction in pupillary diameter at 5 μg eye, though it is not as potent as many other F-type prostaglandins, such as prostaglandin F2α, which achieves the same effect at less than 1 μg eye.

13,14-dihydro-15-keto Prostaglandin E2 (13,14-dihydro-15-keto PGE2) serves as the predominant metabolite of PGE2 in plasma, created through a 15-keto PGE2 intermediate by the action of 15-oxo-PG Δ13 reductase. Unlike its precursor PGE2, this compound exhibits poor binding affinity towards EP2 and EP4 PGE2 receptors (Ki values of 12 and 57 µM, respectively) in CHO cells and fails to stimulate adenylate cyclase activity therein (EC50s >18 and >38 µM, respectively). Concentrations of 13,14-dihydro-15-keto PGE2 are notably higher in the plasma of pregnant women during their third trimester and at labor and delivery stages, whereas its levels are found to be reduced in the tumor tissues of patients with non-small cell lung cancer (NSCLC) compared to adjacent healthy tissue.

11β-13,14-Dihydro-15-keto PGF2α, a PGD2 metabolite in the 15-hydroxy PGDH pathway, is formed in human males upon infusion or inhalation of tritiated PGD2, with peak plasma levels of both 11β-PGF2α and 11β-13,14-dihydro-15-keto PGF2α observed within 10 minutes. In human lung homogenates, PGD2 is metabolized firstly to 11β-PGF2α and subsequently to 11β-15-keto-PGF2α in the presence of NAD+, but not to 11β-13,14-dihydro-15-keto PGF2α. Conversely, guinea pig liver and kidney homogenates can metabolize PGD2 to 11β-13,14-dihydro-15-keto PGF2α via 11β-PGF2α, with both NAD+ and NADP+ being requisite for this conversion.

8-iso Prostaglandin F2β (8-iso PGF2β) is an isomer of PGF2α of non-enzymatic origin. It is one of 64 possible isomers of PGF2α which can be produced by free radical peroxidation of arachidonic acid. 8-iso PGF2β exhibits very weak contraction of human umbilical vein artery and does not promote aggregation of human whole blood. However, 8-iso PGF2β moderately contracts both the canine and porcine pulmonary vein, although the effect is much weaker than that exhibited by other isoprostanes such as 8-iso PGE1, 8-iso PGE2, or 8-iso PGF2α. 8-iso-15-keto PGF2β is a potential metabolite of 8-iso PGF2β via the 15-hydroxy PG dehydrogenase pathway. There are no published reports on the formation or biological activity of 8-iso-15-keto PGF2β.

Prostaglandin A1 (PGA1) was first isolated as a dehydration product of the PGE1 compounds found in human semen. 15-keto PGA1 is a metabolite of PGA1, produced by 15-hydroxy PG dehydrogenase. It can be produced from PGA1 in pig lung, trachea, aorta, and pulmonary artery tissue preparations. 15-keto PGA1, given at a concentration of 6 μM, causes vasoconstriction of rabbit lung that is comparable to that induced by angiotensin II.

Bimatoprost is an F-series prostaglandin (PG) analog approved for use as an ocular hypotensive drug. Oxidation of the C-15 hydroxyl group and amide hydrolysis of Bimatoprost produces 15-keto-17-phenyl trinor PGF2α, a potential metabolite when administered to animals. 15-keto PG analogs can be minor impurities in commercial preparations of corresponding bulk drug compounds. Although much less potent than the parent compound, 15-keto PGs can still produce a small but measurable decrease (1 mm Hg) in intraocular pressure of normal cynomolgus monkeys at a dose of 1 μg eye. 15-keto Latanoprost (15-keto-17-phenyl-13,14-dihydro trinor PGF2α isopropyl ester) acts as a miotic in normal cat eyes, causing an 8 mm reduction in pupillary diameter at 5 μg eye. This is less potent compared to many other F-type PGs; for example, PGF2α induces similar miosis at less than 1 μg eye.

13,14-dihydro-15-keto Prostaglandin F1α (13,14-dihydro-15-keto PGF1α) is a metabolite of PGF1α that has been reported in the rat stomach. The measurement of 13,14-dihydro-15-keto PGF1α can be used as a marker of the in vivo production of PGF1α.

Latanoprost is an F-series prostaglandin (PG) analog which has been approved for use as an ocular hypotensive drug. Oxidation of the C-15 hydroxyl group without isopropyl ester hydrolysis produces 15-keto latanoprost. 15-keto Latanoprost is a potential metabolite of latanoprost when administered to animals. 15-keto Latanoprost is also one of the common minor impurities found in commercial preparations of the bulk drug compound. Although much less potent that the parent compound latanoprost, 15-keto latanoprost still retains the ability to produce a small but measurable decrease (1 mm Hg) in the intraocular pressure of normal cynomolgus monkeys when administered at a dose of 1 μg/eye. 15-keto Latanoprost is also a miotic in the normal cat eye, causing an 8 mm reduction in pupillary diameter at 5 μg/eye. Again, this is not as potent as many other F-type PGs; for example, PGF2α will produce this degree of miosis at a dose of less than 1 μg/eye. Products of β-oxidation account for most of the metabolites of latanoprost recovered in plasma and urine. However, 15-keto latanoprost is a minor metabolite, and one which could be enhanced in situations where β-oxidation is reduced.

Prostaglandin D1 (PGD1) is the theoretical D-series metabolite of dihomo-γ-linolenic acid (DGLA), but to date it has not been isolated as a natural product. It is an inhibitor of ADP-induced platelet aggregation in humans with an IC50 value of 320 ng/ml, about 1/10 as potent as PGD2. 13,14-dihydro-15-keto Prostaglandin D1 (13,14-dihydro-15-keto PGD1) is the theoretical metabolite of PGD1 via the 15-hydroxy PG dehydrogenase metabolic pathway. No biological studies for this compound have been reported.