Absorption, Distribution and Excretion
EL-436 (Fenazaquin, 97.36-98.80% ai; EL-436 uniformly labeled on either the t-butyl-phenyl ring (phenyl; 97.33->99.9%, 4.23 and 5.44 uCi/mg) or the quinazoline-phenyl ring (quinazoline; 98.8-99.2%, 19.8 uCi/mg) was administered to groups of five male and five female Fischer 344 (F344/Crl) rats as a single 1 mg/kg or 30 mg/kg radiolabeled dose. A group of eight male and eight female rats received 14-daily doses of 1 mg/kg unlabeled test material followed by a single radiolabeled gavage dose. An additional group of three male and three female rats received a single 1 mg/kg radiolabel dose to determine elimination of the compound in expired air. Overall recovery of the radiolabel was excellent (89.5-107.7% of the administered dose). Within 48 hours of treatment, approximately 75% of the radiolabel was recovered in the excreta, and by 72 hours after treatment, >84% was recovered. No sex-related differences in elimination were noted. Approximately 20% of the radiolabel was recovered in the urine with the remainder in the feces. Less than 1.6% of the radiolabel was recovered in the residual carcass or tissues and essentially no significant amount of radiolabel was recovered in the expired air. There are no available excretion studies following bile cannulation or intravenous (i.v.) administration to determine test material bioavailability (gastrointestinal absorption). Therefore, while the nearly 20% of the administered dose was absorbed before it was excreted in urine, it is not clear if any or all of the remaining dose (nearly 80%) that was found in feces was actually absorbed prior to its fecal elimination.

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Metabolism / Metabolites
Metabolism involved cleavage of the ether bond, with formation of the 4-hydroxyquinazoline and carboxylic acid derivatives. Other biotransformations included oxidation of one of the methyl groups on the alkyl side chain to produce either an alcohol, which was further metabolised by hydroxylation of the O-ether alkyl moiety, or a carboxylic acid, which was further metabolised by hydroxylation of the 2-position of the quinazoline ring.
EL-436 (Fenazaquin, 97.36-98.80% ai; EL-436 uniformly labeled on either the t-butyl-phenyl ring (phenyl; 97.33->99.9%, 4.23 and 5.44 uCi/mg) or the quinazoline-phenyl ring (quinazoline; 98.8-99.2%, 19.8 uCi/mg) was administered to groups of five male and five female Fischer 344 (F344/Crl) rats as a single 1 mg/kg or 30 mg/kg radiolabeled dose. A group of eight male and eight female rats received 14-daily doses of 1 mg/kg unlabeled test material followed by a single radiolabeled gavage dose. An additional group of three male and three female rats received a single 1 mg/kg radiolabel dose to determine elimination of the compound in expired air. ... In the urine, the primary metabolite was AN-1 (4-(2-hydroxy-1,1-dimethylethyl) phenylacetic acid) (24-29% of total urinary radioactivity) plus numerous minor metabolites. This metabolite was characterized by the absence of protons associated with the quinazoline portion of the molecule, indicating cleavage of the ether bridge. No significant differences between the sexes or dose groups were observed. Four primary metabolites and numerous minor metabolites were found in the feces. The parent compound, fenazaquin, represented 1.2-4.2% of the recovered radioactivity in the single or multiple low-dose groups and 11.5-20.6% of the recovered activity in single high-dose rats. Metabolite F1 (4.6-9.4% of the administered dose) had the phenyl and quinazoline rings and both sets of methylene protons intact, as well as the addition of a single oxygen atom to the phenyl-t-butyl portion of the parent molecule. Metabolite F-1A, a minor metabolite contributing 0.6-2.6% of the radioactivity, was characterized by intact phenyl and quinazoline rings and hydroxylation of the ethoxy bridge. Metabolite F-2 was the primary fecal metabolite identified (16.3-22.8% of the recovered radioactivity) and was similar to metabolite F1, but with the addition of two oxygen atoms and the loss of two hydrogen atoms to form a carboxylic acid on one of the methyl alky groups attached to the phenyl ring. Metabolite F3 contributed 6.5-12.6% of the recovered radioactivity and contained both the phenyl and quinazoline ring systems; however, the quinazoline ring had been hydroxylated and one of the methyl alkyl groups of the phenyl ring had been carboxylated. While the fecal metabolites were likely produced by the liver, it is not possible to exclude metabolism by intestinal microflora. These studies show that radiolabeled fenazaquin is rapidly metabolized and eliminated from male and female rats following treatment with either single or multiple low doses or following a single high dose of the compound. However, there is no information on biliary excretion or fecal/urinary elimination following iv administration.

Non-Human Toxicity Values
LC50 Rat inhalation 1.9 mg/L/ 4 hr
LD50 Rabbit dermal >5000 mg/kg
LD50 Mouse oral (female) 1480 mg/kg
LD50 Mouse oral (male) 2449 mg/kg
For more Non-Human Toxicity Values (Complete) data for Fenazaquin (7 total), please visit the HSDB record page.

Crop Protection Volume 12, Issue 4, June 1993, Pages 255-258

Fenazaquin is a member of quinazolines. It has a role as an acaricide and a mitochondrial NADH:ubiquinone reductase inhibitor.

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Mechanism of Action
Fenazaquin is a miticide that exhibits both contact and ovicidal activity against a broad spectrum of mite and certain insects by inhibiting mitochondrial electron transport at the Complex I site (NADH-ubiquinone reductase).
... In this study, ...the in vitro toxicity and mechanism of action of several putative complex I inhibitors that are commonly used as pesticides. The rank order of toxicity of pesticides to neuroblastoma cells was pyridaben > rotenone > fenpyroximate > fenazaquin > tebunfenpyrad. A similar order of potency was observed for reduction of ATP levels and competition for (3)H-dihydrorotenone (DHR) binding to complex I, with the exception of pyridaben (PYR). Neuroblastoma cells stably expressing the /rotenone/ (ROT)-insensitive NADH dehydrogenase of Saccharomyces cerevisiae (NDI1) were resistant to these pesticides, demonstrating the requirement of complex I inhibition for toxicity. ... PYR was a more potent inhibitor of mitochondrial respiration and caused more oxidative damage than ROT. The oxidative damage could be attenuated by NDI1 or by the antioxidants alpha-tocopherol and coenzyme Q(10). PYR was also highly toxic to midbrain organotypic slices. These data demonstrate that, in addition to ROT, several commercially used pesticides directly inhibit complex I, cause oxidative damage, and suggest that further study is warranted into environmental agents that inhibit complex I for their potential role in Parkinson's Disease.
Parkinson's disease (PD) brains show evidence of mitochondrial respiratory Complex I deficiency, oxidative stress, and neuronal death. Complex I-inhibiting neurotoxins, such as the pesticide rotenone, cause neuronal death and parkinsonism in animal models. We have previously shown that DJ-1 over-expression in astrocytes augments their capacity to protect neurons against rotenone, that DJ-1 knock-down impairs astrocyte-mediated neuroprotection against rotenone, and that each process involves astrocyte-released factors. To further investigate the mechanism behind these findings, we developed a high-throughput, plate-based bioassay that can be used to assess how genetic manipulations in astrocytes affect their ability to protect co-cultured neurons. We used this bioassay to show that DJ-1 deficiency-induced impairments in astrocyte-mediated neuroprotection occur solely in the presence of pesticides that inhibit Complex I (rotenone, pyridaben, fenazaquin, and fenpyroximate); not with agents that inhibit Complexes II-V, that primarily induce oxidative stress, or that inhibit the proteasome. This is a potentially PD-relevant finding because pesticide exposure is epidemiologically-linked with an increased risk for PD. Further investigations into our model suggested that astrocytic GSH and heme oxygenase-1 antioxidant systems are not central to the neuroprotective mechanism.

C20H22N2O

306.4015

306.173

120928-09-8

86356

Colorless crystals

1.1±0.1 g/cm3

461.0±33.0 °C at 760 mmHg

77.5-80 °C

165.1±15.6 °C

0.0±1.1 mmHg at 25°C

1.595

5.54

0

3

5

23

357

0

O(C1C2=C([H])C([H])=C([H])C([H])=C2N=C([H])N=1)C([H])([H])C([H])([H])C1C([H])=C([H])C(=C([H])C=1[H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H]

DMYHGDXADUDKCQ-UHFFFAOYSA-N

InChI=1S/C20H22N2O/c1-20(2,3)16-10-8-15(9-11-16)12-13-23-19-17-6-4-5-7-18(17)21-14-22-19/h4-11,14H,12-13H2,1-3H3

Quinazoline, 4-(2-(4-(1,1-dimethylethyl)phenyl)ethoxy)-

EL 436; EL-436; EL436; XDE 436; XDE-436; XDE436.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)