delta6D in ABMC-7 cells (IC50 = 0.015 μM); delta6D in Liver microsomes (IC50 = 0.56 μM); delta5D in ABMC-7 cells (IC50 = 0.67 μM); delta5D in ABMC-7 cells (IC50 = 3.4 μM)

CP-24879 (hydrochloride) (0-10 μM, 4 days) inhibits Δ6 + Δ5 desaturase activities in a concentration-dependent manner, with a concentration-dependent depletion of AA and a reduction in LTC4 production[1].
CP-24879 (hydrochloride) (0-10 μM, 16 h) exhibits inhibitory effects on triglyceride accumulation brought on by oleic acid in hepatocytes[2].
In a concentration-dependent manner, CP-24879 (hydrochloride) ((0-10 μM, 16 h) inhibits LPS-induced expression of inflammatory cytokines[2].
CP-24879 (hydrochloride) (0-2 μM, 4 h) inhibits desaturase activity and ameliorates ferroptosis[3].

CP-24879 (hydrochloride) (3 mg/kg, IP, three times per day, for six or four days) inhibits Δ6 + Δ5 desaturase activities in vivo, depleting AA in the livers of mice fed chow while preventing repletion in the livers of mice with EFAD[1].
CP-24879 (hydrochloride) (33 mg/kg, IV, once) is cleared quite quickly and has a relatively short half-life[1].

CP-24879 (p-isopentoxyaniline), an aniline derivative, was identified as a mixed delta5/delta6 desaturase inhibitor during the screening of chemical and natural product libraries. In mouse mastocytoma ABMC-7 cells cultured chronically with CP-24879, there was a concentration-dependent inhibition of desaturase activity that correlated with the degree of depletion of AA and decreased production of leukotriene C4 (LTC4). Production of LTC4 was restored by stimulating the cells in the presence of exogenous AA, indicating that endogenous AA was limiting as substrate. [1]

A combined Δ5D/Δ6D inhibitor, CP-24879, significantly reduced intracellular lipid accumulation and inflammatory injury in hepatocytes. Interestingly, CP-24879 exhibited superior antisteatotic and anti-inflammatory actions in fat-1 and ω-3-treated hepatocytes. Hepatocytes were incubated with CP-24879, a specific Δ5/Δ6 desaturase inhibitor,17 CAY10566, a selective Δ9 desaturase inhibitor,18 EPA or resolvin D1 (RvD1) as detailed in online supplementary material and methods[2]

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We next employed SC-26196, a selective FADS2 inhibitor, and CP-24879, a FADS1/FADS2 dual inhibitor. Since several inhibitors often possess intrinsic antioxidant activity, we first measured the scavenging capacity of FADS inhibitors toward 2,2-diphenyl-1-picrylhydrazyl (DPPH) under cell-free conditions. Similar to the results of a previous report, ferrostatin-1 showed free radical scavenging activity at concentrations of 10 to 50 μM under our experimental conditions. While SC-26196 displayed no antioxidant potential, high concentrations of CP-24879 scavenged 60% of the DPPH radical within 30 min (SI Appendix, Fig. S5). To exclude the antioxidant effect of CP-24879, inhibitors were used at a low concentration (5 μM) with no in vitro antioxidant activity in subsequent experiments. The inhibition of desaturase activity by the SC-26196 or CP-24879 treatment dramatically reduced the cytotoxicity induced by RSL3 (Fig. 4 A and B). Furthermore, RSL3-induced lipid peroxidation was noticeably decreased in the presence of SC-26196 or CP-24879 (Fig. 4C). We next assessed whether the PUFA biosynthesis pathway was also required for ferroptosis under GSH depletion conditions. First, cysteine/methionine deprivation-induced ferroptosis was ameliorated in ELOVL5- or FADS1-depleted cells (Fig. 4D). In addition, SC-26196 or CP-24879 suppressed cell death under cysteine/methionine deprivation conditions (Fig. 4E). Based on these data, PUFA biosynthesis enzymes play essential roles in lipid peroxidation and ferroptosis.[3]

In the livers of mice treated chronically with the maximally tolerated dose of CP-24879 (3 mg/kg, t.i.d.), combined delta5/delta6 desaturase activities were inhibited approximately 80% and AA was depleted nearly 50%. These results suggest that delta5 and/or delta6 desaturase inhibitors have the potential to manifest an anti-inflammatory response by decreasing the level of AA and the ensuing production of eicosanoids.[1]

[1]. Identification and characterization of a novel delta6/delta5 fatty acid desaturase inhibitor as a potential anti-inflammatory agent. Biochem Pharmacol. 1998 Apr 1;55(7):1045-58.

[2]. Molecular interplay between Δ5/Δ6 desaturases and long-chain fatty acids in the pathogenesis of non-alcoholic steatohepatitis. Gut. 2014 Feb;63(2):344-55.

[3]. Polyunsaturated fatty acid biosynthesis pathway determines ferroptosis sensitivity in gastric cancer. Proc Natl Acad Sci U S A. 2020;117(51):32433-32442.

The anti-inflammatory properties of essential fatty acid deficiency or n-3 polyunsaturated fatty acid supplementation have been attributed to a reduced content of arachidonic acid (AA; 20:4 n-6). An alternative, logical approach to depleting AA would be to decrease endogenous synthesis of AA by selectively inhibiting the delta5 and/or the delta6 fatty acid desaturase. High-throughput radioassays were developed for quantifying delta5, delta6, and delta9 desaturase activities in vitro and in vivo. CP-24879 (p-isopentoxyaniline), an aniline derivative, was identified as a mixed delta5/delta6 desaturase inhibitor during the screening of chemical and natural product libraries. In mouse mastocytoma ABMC-7 cells cultured chronically with CP-24879, there was a concentration-dependent inhibition of desaturase activity that correlated with the degree of depletion of AA and decreased production of leukotriene C4 (LTC4). Production of LTC4 was restored by stimulating the cells in the presence of exogenous AA, indicating that endogenous AA was limiting as substrate. In the livers of mice treated chronically with the maximally tolerated dose of CP-24879 (3 mg/kg, t.i.d.), combined delta5/delta6 desaturase activities were inhibited approximately 80% and AA was depleted nearly 50%. These results suggest that delta5 and/or delta6 desaturase inhibitors have the potential to manifest an anti-inflammatory response by decreasing the level of AA and the ensuing production of eicosanoids.[1]

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Using oligonucleotide microarray analysis we identified a significant enrichment of genes involved in the multi-step catalysis of long-chain polyunsaturated fatty acids, namely, Δ-5 desaturase (Δ5D) and Δ6D in NASH. Increased expression of Δ5D and Δ6D at both mRNA and protein level were confirmed in livers from mice with high-fat diet-induced obesity and NASH. Gas chromatography analysis revealed impaired desaturation fluxes toward the ω-6 and ω-3 pathways resulting in increased ω-6 to ω-3 ratio and reduced ω-3 index in human and mouse fatty livers. Restoration of hepatic ω-3 content in transgenic fat-1 mice expressing an ω-3 desaturase, which allows the endogenous conversion of ω-6 into ω-3 fatty acids, produced a significant reduction in hepatic insulin resistance, steatosis, macrophage infiltration, necroinflammation and lipid peroxidation, accompanied by attenuated expression of genes involved in inflammation, fatty acid uptake and lipogenesis. These results were mostly reproduced by feeding obese mice with an exogenous ω-3-enriched diet. A combined Δ5D/Δ6D inhibitor, CP-24879, significantly reduced intracellular lipid accumulation and inflammatory injury in hepatocytes. Interestingly, CP-24879 exhibited superior antisteatotic and anti-inflammatory actions in fat-1 and ω-3-treated hepatocytes. Conclusions: These findings indicate that impaired hepatic fatty acid desaturation and unbalanced ω-6 to ω-3 ratio play a role in the pathogenesis of NASH.[2]

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Ferroptosis is an iron-dependent regulated necrosis mediated by lipid peroxidation. Cancer cells survive under metabolic stress conditions by altering lipid metabolism, which may alter their sensitivity to ferroptosis. However, the association between lipid metabolism and ferroptosis is not completely understood. In this study, we found that the expression of elongation of very long-chain fatty acid protein 5 (ELOVL5) and fatty acid desaturase 1 (FADS1) is up-regulated in mesenchymal-type gastric cancer cells (GCs), leading to ferroptosis sensitization. In contrast, these enzymes are silenced by DNA methylation in intestinal-type GCs, rendering cells resistant to ferroptosis. Lipid profiling and isotope tracing analyses revealed that intestinal-type GCs are unable to generate arachidonic acid (AA) and adrenic acid (AdA) from linoleic acid. AA supplementation of intestinal-type GCs restores their sensitivity to ferroptosis. Based on these data, the polyunsaturated fatty acid (PUFA) biosynthesis pathway plays an essential role in ferroptosis; thus, this pathway potentially represents a marker for predicting the efficacy of ferroptosis-mediated cancer therapy.[3]

C11H18CLNO

215.721

215.107

C, 61.25; H, 8.41; Cl, 16.43; N, 6.49; O, 7.42

10141-51-2

10141-51-2

16078965

Brown to black solid powder

322.1ºC at 760 mmHg

154-159ºC

148.6ºC

0.000208mmHg at 25°C

4.076

2

2

4

14

128

0

CC(C)CCOC1=CC=C(C=C1)N.Cl

GFESZSNFRSACMU-UHFFFAOYSA-N

InChI=1S/C11H17NO.ClH/c1-9(2)7-8-13-11-5-3-10(12)4-6-11;/h3-6,9H,7-8,12H2,1-2H3;1H

4-(3-methylbutoxy)aniline;hydrochloride

CP 24879 hydrochloride; CP24879 hydrochloride; CP-24879 hydrochloride; CP 24,879 (hydrochloride); CP-24879 (hydrochloride); 4-(3-methylbutoxy)aniline hydrochloride; Benzenamine, 4-(3-methylbutoxy)-, hydrochloride (9CI); p-(Isoamyloxy)aniline hydrochloride; p-(Isopentyloxy)-aniline; . CP-24879 hydrochloride

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)

DMSO: ~43 mg/mL (~199.3 mM)
Ethanol: ~43 mg/mL (~199.3 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (11.59 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (9.64 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
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.

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