Toxic fluorine compounds. The use of the ω-fluorine atom in the study of the metabolism of fatty acids containing ethyl, <i>n</i>-propyl and isopropyl branches

Pattison, F. L. M.; Peters, D.

doi:10.1042/bj0980689

Cited by 5 publications

(1 citation statement)

References 4 publications

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“…Unfortunately, the half-life of these analogs in mice is short (<1 h) as alkyl moieties are susceptible to ω-oxidation (Table ). To circumvent this issue, fluorine groups were added to potentially enhance the metabolic stability . Interestingly, with the exception of 12bm and 12bu , the combination of halogens and alkyl groups ( 12bn – 12br and 12bt ) led to poor activity similar to the fluorinated alkoxy analogs.…”

Section: Resultsmentioning

confidence: 99%

6-Amino[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol Derivatives as Efficacious Mitochondrial Uncouplers in STAM Mouse Model of Nonalcoholic Steatohepatitis

et al. 2020

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Small molecule mitochondrial uncouplers have recently garnered great interest for their potential in treating nonalcoholic steatohepatitis (NASH). In this study, we report the structure−activity relationship profiling of a 6-amino[1,2,5]oxadiazolo [3,4-b]pyrazin-5-ol core, which utilizes the hydroxy moiety as the proton transporter across the mitochondrial inner membrane. We demonstrate that a wide array of substituents is tolerated with this novel scaffold that increased cellular metabolic rates in vitro using changes in oxygen consumption rate as a readout. In particular, compound SHS4121705 (12i) displayed an EC 50 of 4.3 μM in L6 myoblast cells and excellent oral bioavailability and liver exposure in mice. In the STAM mouse model of NASH, administration of 12i at 25 mg kg −1 day −1 lowered liver triglyceride levels and improved liver markers such as alanine aminotransferase, NAFLD activity score, and fibrosis. Importantly, no changes in body temperature or food intake were observed. As potential treatment of NASH, mitochondrial uncouplers show promise for future development.

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Section: Resultsmentioning

confidence: 99%

6-Amino[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol Derivatives as Efficacious Mitochondrial Uncouplers in STAM Mouse Model of Nonalcoholic Steatohepatitis

et al. 2020

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Esters of Carbonic and Orthocarbonic Acid, Organic Phosphorous, Monocarboxylic Halogenated Acids, Haloalcohols, and Organic Silicon

Christensen

2024

Patty's Toxicology

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Esters of Carbonic and Orthocarbonic Acid, Organic Phosphorous, Monocarboxylic Halogenated Acids, Haloalcohols, and Organic Silicon

Toscano¹,

Coleman²

2012

Patty's Toxicology

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This chapter covers ( 1 ) esters of carbonic and orthocarbonic acid, ( 2 ) esters of organic phosphorous compounds, ( 3 ) esters of monocarboxylic halogenated acids, alkanols, or haloalcohols, and ( 4 ) organic silicon esters. Other classes of esters are summarized in Chapters 57 and 58. Refer to the Introduction in Chapter 57 for a more detailed overview of general properties of esters. Unfortunately, as shown in the two prior chapters, mainly fragmented toxicological evaluations are available for esters. Most of these esters are characterized by low toxicity. Indeed, as expressed in Chapter 57, lethal dose (e.g., LD 50 ) values are frequently difficult or impractical to measure. Localized dermal irritation is one common effect characteristic of exposures to most organic solvents. Few esters are readily absorbed, but there are exceptions, such as tri‐ o ‐cresyl phosphate (TOCP). Several of the halogenated derivatives, such as ethylchloro‐ and ethylbromo‐, are potent lacrimators. Ethyl fluoroacetate and fluoroacetic acid exhibit about the same mode of action, which may indicate that the acetate is rapidly hydrolyzed and metabolized in the mammalian system. The unsaturated carbonates are also associated with high lacrimatory activity. TOCP is an example of an ester that can cause neuropathy in a variety of animal species. The initial weakness and paralysis are normally reversible in early stages, but repeated or massive assaults result in demyelination of the nerve fibers. The mechanism of action is not yet certain, but it appears to involve phosphorylation of proteins. Only selected phosphates exhibit neuropathic effects, including diisopropyl fluorophosphorate and N , N ′‐diisopropyl phosphorodiamidic fluoride. As was expressed in Chapter 57, industrial hygiene evaluation of esters involves collecting and analyzing air samples to determine their airborne concentrations. Published industrial hygiene air sampling and analytical methods, however, are unavailable for most esters. In relation, there are few occupational exposure and biological limits. A list of ester compounds covered in this chapter that have industrial hygiene sampling and analytical methods are presented here along with their respective occupational exposure limits, established by the American Conference of Governmental Industrial Hygienists (ACGIH), the Occupational Safety and Health Administration (OSHA), and the National Institute for Occupational Safety and Health (NIOSH). As stated in Chapter 57, since sampling and analytical methods and occupational exposure limits are subject to periodic revision, the reader is encouraged to refer to current publications of ACGIH, OSHA, and NIOSH.

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Toxic fluorine compounds. The use of the ω-fluorine atom in the study of the metabolism of fatty acids containing ethyl, n-propyl and isopropyl branches

Cited by 5 publications

References 4 publications

6-Amino[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol Derivatives as Efficacious Mitochondrial Uncouplers in STAM Mouse Model of Nonalcoholic Steatohepatitis

6-Amino[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol Derivatives as Efficacious Mitochondrial Uncouplers in STAM Mouse Model of Nonalcoholic Steatohepatitis

Esters of Carbonic and Orthocarbonic Acid, Organic Phosphorous, Monocarboxylic Halogenated Acids, Haloalcohols, and Organic Silicon

Esters of Carbonic and Orthocarbonic Acid, Organic Phosphorous, Monocarboxylic Halogenated Acids, Haloalcohols, and Organic Silicon

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