A nonspecific CYP450 inhibitor
IC50: in the μM range when tested using human liver microsomes
SKF 525A is a cytochrome P (CYP)450 inhibitor.
Cytochromes P450 (CYPs) use various molecules as substrates in enzymatic reactions. CYPs are the metabolic oxidase enzymes in electron transfer chains, categorized as P450-containing systems.
In vitro: Previous study found that when incubated with human liver microsomes, SKF525A could undergo CYP-dependent oxidative N-deethylation to its secondary amine metabolite SKF8742. In addition, SKF525A and its metabolite and primary amine analog all inhibited CYP2B6-, CYP2C9-, CYP2C19-, CYP2D6-, as well as CYP3A-selective reactions to various degrees but had little effect on CYP1A2, CYP2A6, and CYP2E1 reactions [1].
In vivo: Animal study found that SKF 525A at 1.5-9 mg/kg could reduce or abolish the hypertensive effect of McN-A-343, DMPP and nicotine, but could neither noticeably affect the hypertensive effect of tyramine, adrenaline and noradrenaline, nor the hypotensive effect of acetylcholine and orciprenaline. Thus, SKF 525A was able to block the rat sympathetic ganglia and the adrenal medulla and such blockade was non-specific. Moreover, the blockade might result from the stabilizing effect of SKF 525A on postsynaptic membranes of the sympathetic ganglia and the adrenal medulla [2].
Clinical trial: Up to now, SKF 525A is still in the preclinical development stage.
参考文献:
[1] M.? R. Franklin and L. B. Hathaway. 2-Diethylaminoethyl-2,2-diphenylvalerate-HCl (SKF525A) revisited: Comparative cytochrome P450 inhibition in human liver microsomes by SKF525A, its metabolites, and SKF-acid and SKF-alcohol. Drug Metabolism and Disposition 36(12), 2539-2546 (2008).
[2] Krsti MK.? Blockade by SKF 525A of the rat sympathetic ganglia and the adrenal medulla. Arch Int Pharmacodyn Ther. 1976 Sep;223(1):64-70.
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