After oral administration of 8-methoxypsoralen to rats, metabolites in urine were; 8-hydroxypsoralen, 5-hydroxy-8-methoxypsoralen, 5,8-dioxopsoralen, 5,8-dihydroxypsoralen, 4,6,7-trihydroxy-5-coumaranoyl-beta-acrylic acid, 4,6-dihydroxy-7-methoxy-5-coumaranoyl-beta-acrylic acid.
Although the exact metabolic fate of methoxsalen has not been fully established, the drug is rapidly and apparently almost completely metabolized. Methoxsalen is demethylated to 8-hydroxypsoralen (8-HOP), and methoxsalen and 8-HOP are conjugated with glucuronic acid and sulfate; other unidentified metabolites have also been detected. Methoxsalen and 8-hydroxypsoralen and their conjugates are excreted in urine. Following oral administration of methoxsalen, 80-90% of the drug is excreted in urine within 8 hours as hydroxylated, glucuronide, and sulfate metabolites; less than 0.1% of a dose is excreted in urine as unchanged drug. About 95% of the drug is excreted in urine within 24 hours as metabolites.
Methoxsalen is extensively metabolized, and less than 2% of the drug is excreted unchanged in the urine. Four urinary metabolites were isolated; 3 of them resulted from opening of the furan ring: these are 7-hydroxy-8-methoxy-2-oxo-2H-1-benzopyran-6-acetic acid, alpha,7-dihydroxy-8-methoxy-2-oxo-2H-1-benzopyran-6-acetic acid, and an unknown conjugate of the former at the 7-hydroxy position. The fourth metabolite, formed by opening of the pyrone ring, is an unknown conjugate of (Z)-3-(6-hydroxy-7-methoxybenzofuran-5-yl)-2-propenoic acid.
Route of Elimination: In both mice and man, methoxsalen is rapidly metabolized. Approximately 95% of the drug is excreted as a series of metabolites in the urine within 24 hours (Pathak et al. 1977).
Half Life: Approximately 2 hours
IDENTIFICATION AND USE: 8-Methoxypsoralen (8-MOP) belongs to a group of compounds known as psoralens, or furocoumarins. It is used as suntan accelerator and sunburn protector. 8-MOP is used for photochemotherapy (PUVA, 8-MOP with long wave UVA radiation) for psoriasis. It is also used in conjunction with long wavelength UVA or sunlight to repigment vitiliginous skin in patients with idiopathic vitiligo. Oral 8-MOP is used in conjunction with photopheresis for the palliative treatment of the skin manifestations of cutaneous T-cell lymphoma. HUMAN STUDIES: In Indian patients treated for vitiligo, 12 percent developed keratoses, but not cancer. Of 52 patients under continued PUVA treatment,12 subjects had small superficial dermal amyloid deposits. Three of 20 healthy volunteers given increasing doses of topically applied 1% 8-MOP 3 times a week plus UV light developed photoallergy. Other adverse dermatologic effects associated with PUVA therapy include skin freckling, hypopigmentation, uneven or excessive tanning, dry skin, vesiculation and bullae formation, generalized exfoliation, nonspecific rash, urticaria, miliaria, folliculitis, acneiform eruption, aggravation or extension of psoriasis, hyperpigmentation of psoriatic lesions, cutaneous tenderness, severe skin pain, onycholysis, pigmentation of the nails, and exacerbation of latent photosensitive dermatoses. Kaposi's varicelliform eruption was reported after the initiation of PUVA therapy. Phototoxic reactions including severe edema and erythema, and painful blistering, burning, and peeling of skin may occur with methoxsalen and conventional UV light. In addition, PUVA therapy has produced severe burns requiring hospitalization, and marked hyperpigmentation and aging of skin. Nausea is the most common adverse effect of oral 8-MOP, occurring in about 10% of patients. GI disturbances may also occur with PUVA therapy utilizing 8-MOP. Pruritus occurs in about 10% of patients treated with PUVA therapy utilizing 8-MOP. A case of a bilateral macular toxicity was reported in a male treated with 8-MOP for vitiligo. A 59-year-old white woman developed a toxic hepatitis while on oral 8-MOP PUVA treatment. There are reports of carcinomas in patients treated with 8-MOP. In a cohort study of 1373 patients treated with 8-MOP plus UV light for psoriasis, 30 patients developed 19 basal-cell carcinomas and 29 squamous-cell carcinomas of the skin. There is increased risk for melanoma in PUVA patients. Some patients developing melanoma did so even after having ceased PUVA therapy over 5 years earlier. Treatment with 8-MOP plus UV irradiation resulted in significant increase of chromosomal aberrations in lymphocyte chromosomes of 1/8 patients, slight but non-significant increases in 6 and no increase in one patient, sister chromatid exchanges were also observed. No chromosome aberrations or sister chromatid exchanges were observed in psoriasis patients treated with the combination but when white blood cells removed from patients after treatment were irradiated with UV light in vitro, there was a significant increase in sister chromatid exchanges. More point mutations, as indicated by the increased incidence of 6-thioguanine-resistant lymphocytes, were observed in patients treated with psoralen drugs and UV irradiation than in healthy controls. ANIMAL STUDIES: Severe reactions were reported in guinea pigs given 40 mg of 8-MOP by i.p. injection one hour before they were exposed to long wavelength UV continuously for 24 hours. White guinea pigs developed ulceration of the lids, edema of the corneas, congestion of iris vessels, permanently dilated pupils, and multiple anterior cortical punctate opacities in the lenses. In black guinea pigs the lids and iris were less damaged. Guinea pigs given 8-MOP at 80 to 100 mg/kg showed no damage to the eyes unless they were also exposed to long wavelength UV. Topical or i.p. 8-MOP has been reported to be a potent photocarcinogen in albino mice and hairless mice. However, 8-MOP given by the oral route to albino mice exerted a protective effect against UV carcinogenesis. Mice given 8-MOP in their diet showed 38% ear tumors 180 days after the start of UV therapy compared to 62% for controls. Hairless mice were given daily skin applications of 40 ug of 8-MOP 30-60 minutes before a whole body 10 minute exposure to UV light (300-400 nm) 5 days a week. The number of tumors per mouse was significantly higher in animals given 8-MOP plus UV. Most of the tumors were squamous cell carcinomas; others were fibrosarcomas, lymphosarcomas, sebaceous adenomas and hemangiomas. In mice, ip injection of 4 mg/kg bw 8-MOP followed by exposure to long wave UV irradiation (320-400 nm) resulted in severe toxic effects including erythema, burns and liver damage. In 2 yr gavage studies in male rats using 8-MOP without UV radiation reported increased incidences of tubular cell hyperplasia, adenomas, and adenocarcinomas of the kidney and carcinomas of the Zymbal gland. Dose related nonneoplastic lesions in male rats included increased severity of nephropathy and mineralization of the kidney and forestomach lesions. There was no evidence of carcinogenic activity of 8-MOP for female rats given the chemical at 37.5 or 75 mg/kg/day for 2 yr. Doses of 80 to 160 mg/kg/day given during organogenesis caused significant fetal toxicity in rats, which was associated with significant maternal weight loss, anorexia and increased relative liver weight. 8-MOP caused an increase in skeletal malformation and variations at doses of 80 mg/kg/day and above. 8-MOP was mutagenic in the Ames test with metabolic activation. In the absence of metabolic activation and UV light, 8-MOP was clastogenic in vitro (sister chromatid exchange and chromosome aberrations in Chinese hamster ovary cells). 8-MOP also caused DNA damage, interstrand cross-links and errors in DNA repair.
Methoxsalen is a cholinesterase or acetylcholinesterase (AChE) inhibitor. A cholinesterase inhibitor (or 'anticholinesterase') suppresses the action of acetylcholinesterase. Because of its essential function, chemicals that interfere with the action of acetylcholinesterase are potent neurotoxins, causing excessive salivation and eye-watering in low doses, followed by muscle spasms and ultimately death. Nerve gases and many substances used in insecticides have been shown to act by binding a serine in the active site of acetylcholine esterase, inhibiting the enzyme completely. Acetylcholine esterase breaks down the neurotransmitter acetylcholine, which is released at nerve and muscle junctions, in order to allow the muscle or organ to relax. The result of acetylcholine esterase inhibition is that acetylcholine builds up and continues to act so that any nerve impulses are continually transmitted and muscle contractions do not stop. Among the most common acetylcholinesterase inhibitors are phosphorus-based compounds, which are designed to bind to the active site of the enzyme. The structural requirements are a phosphorus atom bearing two lipophilic groups, a leaving group (such as a halide or thiocyanate), and a terminal oxygen. The mechanism of action many furocoumarins is based on their ability to form photoadducts with DNA and other cellular components such as RNA, proteins, and several proteins found in the membrane such as phospholipases A2 and C, Ca-dependent and cAMPdependent protein-kinase and epidermal growth factor. Furocoumarins intercalate between base pairs of DNA and after ultraviolet-A irradiation, giving cycloadducts. (L579).
In both mice and man, methoxsalen is rapidly metabolized. Approximately 95% of the drug is excreted as a series of metabolites in the urine within 24 hours (Pathak et al. 1977).
After oral admin of (3)H 8-methoxypsoralen to rats, it was absorbed rapidly and max blood level was observed at 10 min. Moderate radioactivity was found in liver and kidneys at 0.5-4 hr, and low levels in other tissues. ... 62.8% of radioactivity was excreted in urine and 20.4% in feces within 24 hr and 65.1% and 21.9% during 6 days, respectively. In bile, 30.0% was also recovered within 24 hr; this passed through enterohepatic circulation.
Improvement in effective bioavailability of methoxsalen was achieved when it was administered to rats and dogs in solution as compared to suspension. Much earlier and higher peak levels were observed for the solution in both animals.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
Max serum concentration /in patients/ occurred between 0.5 and 2 hr after oral administration of 0.6 mg/kg methoxsalen. There was significant negative correlation between logarithm of serum concentration and minimum phototoxic dose. Hence degree of photosensitivity appears to be related to serum level of methoxsalen.
最大血药浓度出现在患者口服0.6毫克/千克甲氧沙林后0.5到2小时之间。血药浓度的对数与最小光毒性剂量之间存在显著负相关。因此，光敏感度的程度似乎与甲氧沙林血药水平有关。
Max serum concentration /in patients/ occurred between 0.5 and 2 hr after oral administration of 0.6 mg/kg methoxsalen. There was significant negative correlation between logarithm of serum concentration and minimum phototoxic dose. Hence degree of photosensitivity appears to be related to serum level of methoxsalen.
Single iv doses of 5 mg/kg body weight (14)C methoxsalen to dogs disappeared rapidly from plasma, although small levels of radioactivity persisted for 5 weeks after administration. Evidence suggested that the persistent plasma radioactivity was due to a metabolite bound to plasma protein. Elimination occurred in both urine and bile; 45% of the dose appeared in the urine and 40% in the feces within 72 hrs of administration.
Synthesis of 8-geranyloxypsoralen analogues and their evaluation as inhibitors of CYP3A4
摘要：
Furanocoutnarins have been shown to inhibit CYP3A4 in vitro with varying degrees of potency [Pharmacogeneties 1997, 7, 391-396; Chem. Res. Toxicol. 1998, 11, 252-259; Drug Metab. Dispos. 1997, 25, 1228-1233; Br. J. Pharmacol 2000, 130, 13691377]. In this study, we report the effects of a series of novel furanocoumarins based on the naturally Occurring derivative 8-geranylepoxypsoralen which has been shown to be a more potent inhibitor of CYP3A4 than its 5-position-substituted counterpart bergamottin [Drug Metab. Dispos. 2000, 28, 766-771; Jpn. J. Pharmacol. 2000, 82, 122-129]. Compounds were designed, synthesised and tested for their ability to inhibit CYP3A4 activity in human liver microsomes using testosterone as the marker Substrate. Both the saturated and unsaturated phenolic furanocoumarin derivatives were found to be inactive. However, the 8-alkyloxy-furanocoumarin analogues were shown to inhibit CYP3A4 activity in a dose dependent manner, with IC50 values ranging from 0.78 +/- 0.11 to 3.93 +/- 0.53 mu M. The reduced furan derivative dihydro-8-geranyloxypsoralen showed a 4-fold decrease in inhibitory potency, suggesting that the furan moiety plays a role in the interaction between these compounds and CYP3A4. (c) 2006 Elsevier Ltd. All rights reserved.
The present invention provides AA targeting compounds which comprise AA targeting agent-linker conjugates which are linked to a combining site of an antibody. Various uses of the compounds are provided, including methods to treat disorders connected to abnormal angiogenesis.
The present invention is directed to cyclopropylamine derivatives which are LSD1 inhibitors useful in the treatment of diseases such as cancer.
本发明涉及环丙胺衍生物，这些衍生物是LSD1抑制剂，可用于治疗癌症等疾病。
[EN] NOVEL SMALL MOLECULE INHIBITORS OF TEAD TRANSCRIPTION FACTORS<br/>[FR] NOUVEAUX INHIBITEURS À PETITES MOLÉCULES DE FACTEURS DE TRANSCRIPTION TEAD
申请人：MASSACHUSETTS GEN HOSPITAL
公开号：WO2020190774A1
公开（公告）日：2020-09-24
The present disclosure compounds, as well as their compositions and methods of use. The compounds inhibit the activity of the TEAD transcription factor, and are useful in the treatment of diseases related to the activity of TEAD transcription factor including, e.g., cancer and other diseases.
[EN] COMBINATIONS OF INHIBITORS OF IRAK4 WITH INHIBITORS OF BTK<br/>[FR] COMBINAISONS D'INHIBITEURS DE L'IRAK4 À L'AIDE D'INHIBITEURS DE LA BTK
申请人：BAYER PHARMA AG
公开号：WO2016174183A1
公开（公告）日：2016-11-03
The present application relates to novel combinations of at least two components, component A and component B: · component A is an IRAK4-inhibiting compound of the formula (I) as defined herein, or a diastereomer, an enantiomer, a metabolite, a salt, a solvate or a solvate of a salt thereof; · component B is a BTK-inhibiting compound, or a pharmaceutically acceptable salt thereof; and, optionally, · one or more components C which are pharmaceutical products; in which one or two of the above-defined compounds A and B are optionally present in pharmaceutical formulations ready for simultaneous, separate or sequential administration, for treatment and/or prophylaxis of diseases, and to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases, especially for treatment and/or prophylaxis of endometriosis, lymphoma, macular degeneration, COPD, neoplastic disorders and psoriasis.
The present invention provides a compound of Formula (I) or the pharmaceutically acceptable salts, esters, and prodrugs thereof, which are ERK2 inhibitors. The invention also provides a pharmaceutical composition comprising an effective amount of at least one compound of Formula (I) and a pharmaceutically acceptable carrier. The invention also provides a pharmaceutical composition comprising an effective amount of at least one compound of Formula (I) and an effective amount of at least one other pharmaceutically active ingredient (such as, for example, a chemotherapeutic agent), and a pharmaceutically acceptable carrier.
