Methods and compositions for gamma-glutamyl cycle modulation
The present disclosure provides pharmaceutical compositions comprising Gamma-glutamyl cycle inhibitors (GGCI) and certain pharmaceutically acceptable salts thereof, and methods of use.
1 . A compound represented by formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R is independently selected from optionally substituted aryl, heteroaryl, para- methoxyphenyl, ortho-hydroxy phenyl, and phenyl;
R 2 is COOH;
R 3 and R 4 are each independently selected from methyl, ethyl, and propyl; and
* is independently selected from selenium and tellurium.
2 . A pharmaceutical composition consisting essentially of a stereoisomeric compound, or salt thereof, of claim 1 , and a pharmaceutically acceptable excipient,
wherein the pharmaceutically acceptable excipient is selected from sterile saline, buffers, antioxidants, preservatives, alkyl parabens, sugars, and non-ionic surfactants.
3 . A composition for selectively inhibiting the synthesis of glutamic acid in the gamma-glutamyl cycle in tumor cells, comprising a therapeutically effective amount of a compound of claim 1 .
4 . The compound of claim 1 or a pharmaceuitcally acceptable salt thereof, wherein R 3 and R 4 are each methyl.
5 . A pharmaceutical composition consisting essentially of a stereoisomeric compound of claim 4 or a pharmaceutically acceptable salt thereof,
and comprising a pharmaceutically acceptable excipient;
wherein the pharmaceutically acceptable excipient is selected from sterile saline, buffers, antioxidants, preservatives, alkyl parabens, hydrophilic polymers, sugars, and non-ionic surfactants.
6 . The pharmaceutical composition of claim 5 , wherein the composition is in a form selected from: tablets, capsules, solutions and suspensions.
7 . The pharmaceutical composition of claim 5 , wherein the buffer is selected from: phosphate, citrate, ascorbate, and Ringer's solution.
8 . A pharmaceutical composition consisting essentially of a stereoisomeric compound represented by formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R is independently selected from optionally substituted aryl, heteroaryl, para- methoxyphenyl, ortho-hydroxy phenyl, and phenyl;
R 2 is COOH;
R 3 and R 4 are each independently selected from methyl, ethyl, and propyl; and
* is independently selected from sulfur, selenium and tellurium;
and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient is:
selected from an antioxidant selected from ascorbic acid and methionine;
a preservative selected from octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl alcohol, and benzyl alcohol;
an alkyl paraben selected from methyl paraben and propyl paraben;
a sugar selected from: glucose, mannose, sucrose, mannitol, trehalose, sorbitol, and dextrin; or
a non-ionic surfactant selected from: Tween (Polyoxyethylene (20) sorbitan monolaurate), Pluronic (poly (ethylene oxide)-co-(poly (propylene oxide))), and polyethylene glycol.
9 . The pharmaceutical composition of claim 5 , wherein the hydrophilic polymer is polyvinylpyrrolidone.
10 . The pharmaceutical composition of claim 5 , wherein the pharmaceutically acceptable salt is selected from: sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, fluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate “mesylate”, ethansulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate, which is 1′-methylene-bis(2-hydroxy-3-napthoate).
11 . A pharmaceutical composition consisting essentially of a stereoisomeric compound of claim 1 and an anti-hormonal agent.
12 . The pharmaceutical composition of claim 11 , wherein the anti-hormonal agent is selected from: anti-estrogens and selective estrogen receptor modulators.
13 . The pharmaceutical composition of claim 12 , wherein the anti-hormonal agent is selected from: tamoxifen, tamoxifen citrate, raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene citrate.