A novel active metabolite of the anti-cancer drug Tamoxifen. It showed potent ER binding property, blocked estrogen stimulated growth of breast cancer cell and half maximal inhibition of estrogen responsive gene expression in ER pos. human breast ca
A novel active metabolite of the anti-cancer drug Tamoxifen (T006000). It showed potent ER binding property, blocked estrogen stimulated growth of breast cancer cell and half maximal inhibition of estrogen responsive gene expression in ER pos. human breast cancer cell line.
Avacopan is approved for the treatment of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). These two diseases are the two most common forms of non-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, a systemic autoimmune disease.
ChEBI: 4-Hydroxy-N-desmethyltamoxifen is a stilbenoid.
(Z)-Endoxifen (endoxifen) is an active tamoxifen metabolite generated via actions of cytochrome P450 (CYP) enzymes CYP3A4/5 and CYP2D6. Endoxifen is more potent than tamoxifen as a selective estrogen receptor modulator (SERM) both in vitro and in vivo with good pharmacokinetics and oral availability (∼80% MCF-7 tumor growth inhibition with 4-8 mg/kg/day endoxifen or 20 mg/kg/day tamoxifen in mice via p.o.). Endoxifen also exhibits 4-fold higher PKC inhibitory potency than tamoxifen and can overcome tamoxifen resistance due to cytochrome CYP2D6 polymorphism.
The synthetic route for Avacopan is shown below: first, ethyl 3-(4-nitrophenyl)-3-oxopropanoate 18.1 was reacted with acrolein diethyl acetal in the presence of (R)-(-)-2-phenylglycidinol 18.2 to give tetrahydropyridine 18.3. Next, stereoselective olefinic reduction was carried out by palladium-catalysed hydrogenation ( possibly due to the stereoisomerism introduced by 18.2), along with nitro reduction and removal of the bis-epoxazole fragment to form piperidine. The crude amino ester was obtained as 78% ee by reductive amination with cyclopentanone. Subsequently, the 1:2 amine:salt adduct 18.4 was obtained in 70% yield from 18.3 by forming a salt with (-)-O,O′-di-p-tolyl-L-tartaric acid with an ee value >99:1. Saltolysis and an acylation reaction with 2-fluoro-6-methylbenzoyl chloride 18.5 yielded the amide 18.6. Finally, the amide 18.6 was formed via a Lewis acid-mediated amidation reaction with 4-methyl-5-trifluoromethylaniline 18.7, Avacopan (18) was obtained in 80% yield with de and ee >99.8%.
Z-Endoxifen (Z-isomer) (5 mg/kg/day, s.c., gradual drug release every 30 days, pellets replaced every 90 days) effectively prevents breast cancer in the C3(1)-TAg mouse model[3].
Z-Endoxifen (50 mg/kg, p.o., 5 times a week for 4 weeks) shows better antitumor efficacy in the MCF7LR resistant mouse model[4].
Z-Endoxifen (75 mg/kg, p.o., once daily for 4 weeks) shows strong antitumor activity in the MCF7AC1 mouse breast cancer model[4].
| Animal Model: | C3(1)-TAg mouse mammary tumorigenesis model, developed by breeding FVB/NJ females with FVB/C3(1)-TAg males (8 weeks), resulting in SV40 T-antigen expression in mammary gland cells and tamoxifen resistance[3] |
| Dosage: | 5 mg/kg/day |
| Administration: | Subcutaneously implanted pellets, replaced every 90 days, with each pellet designed to release the drug gradually over 30 days. |
| Result: | Significantly increased tumor latency and reduced tumor growth. |
| Animal Model: | MCF7LR mouse breast cancer model, simulating endocrine-resistant breast cancer, developed by prolonged exposure to Letrozole[4] |
| Dosage: | Z-Endoxifen: 50 mg/kg (Tamoxifen (HY-13757A): 500 μg/day, Exemestane (HY-13632): 250 μg/day，Everolimus (HY-10218): 2.5 mg/day) |
| Administration: | Z-Endoxifen: oral gavage (p.o.), the others administered subcutaneously, 5 times a week for 4 weeks |
| Result: | Significantly reduced tumor volume in the MCF7LR resistant model compared to Tamoxifen and Exemestane. |
