トリメトレキサート

5-メチル-6-[[(3,4,5-トリメトキシフェニル)アミノ]メチル]-2,4-キナゾリンジアミン · 5-メチル-6-[(3,4,5-トリメトキシフェニルアミノ)メチル]キナゾリン-2,4-ジアミン · 5-メチル-6-(3,4,5-トリメトキシアニリノメチル)キナゾリン-2,4-ジアミン · 5-メチル-6-[[(3,4,5-トリメトキシフェニル)アミノ]メチル]キナゾリン-2,4-ジアミン · トリメトレキサート · 2,4-ジアミノ-5-メチル-6-[(3,4,5-トリメトキシアニリノ)メチル]キナゾリン · 2,4-ジアミノ-5-メチル-6-(3,4,5-トリメトキシフェニルアミノメチル)キナゾリン · 5-メチル-6-(3,4,5-トリメトキシフェニルアミノメチル)キナゾリン-2,4-ジアミン

https://huagongshe.com/ja/chemical/5583

識別子と物理属性

CAS No.	52128-35-5
分子式	C19H23N5O3
平均分子量	369.4 g/mol
単同位体質量	369.1800896 g/mol
SMILES	COc1cc(NCc2ccc3nc(N)nc(N)c3c2C)cc(OC)c1OC
InChIKey	NOYPYLRCIDNJJB-UHFFFAOYSA-N
PubChem CID	5583
ChEMBL	CHEMBL119
ChEBI	CHEBI:9737
DTXSID	DTXSID3023714
現地名	トリメトレキサート

化学・物理的性質

XLogP	2.5
極性表面積	118
水素結合供与体数	3
水素結合受容体数	8
回転可能結合数	6
重原子数	27
形式電荷	0
複雑度	457
医薬品	Pharmaceuticals -> Listed in ZINC15
LogP（分配係数）	22.55
溶解度	Tan colored solidsolubility in water: > 50 mg/ml /Trimetrexate D-glucuronate/3.09e-02 g/LWater 1 - 2 (mg/mL)pH 4 Acetate buffer < 1 (mg/mL)pH 9 Acetate buffer < 1 (mg/mL)DMSO : ≥ 61.5 mg/mL (166.48 mM)
融点	215-217 °C215 - 217 °C
Physical Description	Solid
Stability/Shelf Life	Bulk: A sample stored at 60 °C for 30 days showed no decomposition (UV, HPLC). Solution: A solution in 5% methanol (0.5 mg/mL) showed no decomposition after 9 days (UV). A solution in 5% dimethylacetamide /pH 4 acetate buffer showed no decomposition after 48 hours(HPLC).
Dissociation Constants	8.0
Other Experimental Properties	Crystals from aqueous acetic acidmp: 215-217 °Cpoorly sol in water. /Trimetrexate monoacetate monohydrate/
沸点	647.0±65.0 °C(Predicted)
密度	1.305±0.06 g/cm3(Predicted)
貯蔵条件	2-8°C(protect from light)
外観・状態	Solid
pKa（酸解離定数）	8.09±0.30(Predicted)
色	Light yellow to green yellow

安全性と法規制

その他の安全情報	IMAP assessments - 2,4-Quinazolinediamine, 5-methyl-6-[[(3,4,5-trimethoxyphenyl)amino]methyl]-: Environment tier I assessment
FDA 要件	Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended21 U.S.C. 321-392).
Hazardous Reactivities and Incompatibilities	Trimetrexate is incompatible with solutions containing chloride ions. Only dextrose 5% in water is recommended for intravenous infusion.Trimetrexate and leucovorin must be administered separately, as a precipitate forms instantly when these 2 drugs added together.
Treatment	In the event of overdose, Trimetrexate should be stopped and leucovorin should be administered at a dose of 40 mg/m2 every 6 hours for 3 days. (L1712)
健康影響	Antibiotic resistance
Hepatotoxicity	When given without leucovorin protection, trimetrexate therapy is associated with a moderate rate of serum enzyme elevations, serum ALT or AST elevations above 5 times ULN in up to 20% of patients. When given with leucovorin, however, trimetrexate has fewer side effects although serum enzyme elevations can still occur. In clinical trials in patients with HIV infection and Pneumocystis jirovecii pneumonia, ALT elevations above 5 times ULN occurred in 1% to 8% of patients, but were usually no more frequent than with standard therapy using trimethoprim with sulfamethoxazole. The elevations were typically transient, without accompanying symptoms or jaundice and resolved or improved despite continuation of therapy. No instances of clinically apparent acute liver injury attributed to trimetrexate have been reported in the literature. In addition, trimetrexate has not been linked to sinusoidal obstruction syndrome or to reactivation of hepatitis B. Nevertheless, trimetrexate probably has hepatotoxic potential, but because it has limited use, is given for short periods of time and is administered with leucovorin, it has not been convincingly linked to cases of clinically apparent liver injury with jaundice.
暴露経路	Intravenous injection
毒性の概要	In vitro studies have shown that trimetrexate is a competitive inhibitor of dihydrofolate reductase (DHFR) from bacterial, protozoan, and mammalian sources. DHFR catalyzes the reduction of intracellular dihydrofolate to the active coenzyme tetrahydrofolate. Inhibition of DHFR results in the depletion of this coenzyme, leading directly to interference with thymidylate biosynthesis, as well as inhibition of folate-dependent formyltransferases, and indirectly to inhibition of p.r.n. biosynthesis. The end result is disruption of DNA, RNA, and protein synthesis, with consequent cell death.

用途

説明

Trimetrexate (TMQ) has been approved for the treatment of Pneumocystis carinii in patients with AIDS and also exhibits antiprotozoal activity against Trypanosoma cruzi . The drug is available as a single-ingredient medication, but it can be administered along with folinic acid in much the same way that methotrexate is administered with calcium leucovorin in cancer chemotherapy. Trimetrexate is a derivative of methotrexate.

使用

Trimetrexate is an FDA-approved drug which selectively inhibits Streptococcus mutans through targeting dihydrofolate reductase (DHFR).

一般的な説明

The drug is available as a lyophilized powder in 5- or 30-mgvials for IV use. The drug is used to treat colorectal cancer,head and neck cancer as well as NSCLC. The mechanism ofaction of trimetrexate involves folate antagonism and inhibitionof thymidylate synthesis. Trimetrexate does not formintracellular polyglutamate adducts as does methotrexateand other related compounds. Resistance can occur by increasedexpression of the target enzyme, decreased bindingaffinity for the target enzyme, or decreased intracellulardrug transport. Trimetrexate is administered only by the IVroute and distributed throughout the body with extensivebinding to plasma proteins. The major catabolic pathwaysinvolve O-demethylation followed by glucuronide conjugation.The drug interaction and toxicity profiles are similar tothose for methotrexate.