The recognition that rapidly proliferating cancer cells rely heavily on glutamine for their survival and growth has renewed interest in the development of glutamine antagonists for cancer therapy. Glutamine plays a pivotal role as a carbon source for synthesizing lipids and metabolites through the TCA cycle, as well as a nitrogen source for synthesis of amino acid and nucleotides. Numerous studies have explored the significance of glutamine metabolism in cancer, providing a robust rationale for targeting this metabolic pathway in cancer treatment. The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) has been explored as an anticancer therapeutic for nearly six decades. Initial investigations revealed remarkable efficacy in preclinical studies and promising outcomes in early clinical trials. However, further advancement of DON was hindered due to dose-limiting gastrointestinal (GI) toxicities as the GI system is highly dependent on glutamine for regulating growth and repair. In an effort to repurpose DON and mitigate gastrointestinal (GI) toxicity concerns, prodrug strategies were utilized. These strategies aimed to enhance the delivery of DON to specific target tissues, such as tumors and the central nervous system (CNS), while sparing DON delivery to normal tissues, particularly the GI tract. When administered at low daily doses, optimized for metabolic inhibition, these prodrugs exhibit remarkable effectiveness without inducing significant toxicity to normal tissues. This approach holds promise for overcoming past challenges associated with DON, offering an avenue for its successful utilization in cancer treatment.

• MeSH
• antitumorózní látky farmakologie   terapeutické užití   MeSH
• diazooxonorleucin * farmakologie   terapeutické užití   MeSH
• glutamin metabolismus   MeSH
• lidé MeSH
• nádory * farmakoterapie   metabolismus   MeSH
• prekurzory léčiv * farmakologie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) exhibits remarkable anticancer efficacy; however, its therapeutic potential is hindered by its toxicity to gastrointestinal (GI) tissues. We recently reported the discovery of DRP-104, a tumor-targeted DON prodrug with excellent efficacy and tolerability, which is currently in clinical trials. However, DRP-104 exhibits limited aqueous solubility, and the instability of its isopropyl ester promoiety leads to the formation of an inactive M1-metabolite, reducing overall systemic prodrug exposure. Herein, we aimed to synthesize DON prodrugs with various ester and amide promoieties with improved solubility, GI stability, and DON tumor delivery. Twenty-one prodrugs were synthesized and characterized in stability and pharmacokinetics studies. Of these, P11, tert-butyl-(S)-6-diazo-2-((S)-2-(2-(dimethylamino)acetamido)-3-phenylpropanamido)-5-oxo-hexanoate, showed excellent metabolic stability in plasma and intestinal homogenate, high aqueous solubility, and high tumor DON exposures and preserved the ideal tumor-targeting profile of DRP-104. In conclusion, we report a new generation of glutamine antagonist prodrugs with improved physicochemical and pharmacokinetic attributes.

• MeSH
• diazooxonorleucin farmakokinetika   MeSH
• estery terapeutické užití   MeSH
• glutamin MeSH
• lidé MeSH
• nádory * farmakoterapie   MeSH
• prekurzory léčiv * chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

6-Diazo-5-oxo-l-norleucine (DON) is a glutamine antagonist that suppresses cancer cell metabolism but concurrently enhances the metabolic fitness of tumor CD8+ T cells. DON showed promising efficacy in clinical trials; however, its development was halted by dose-limiting gastrointestinal (GI) toxicities. Given its clinical potential, we designed DON peptide prodrugs and found DRP-104 [isopropyl(S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)-propanamido)-6-diazo-5-oxo-hexanoate] that was preferentially bioactivated to DON in tumor while bioinactivated to an inert metabolite in GI tissues. In drug distribution studies, DRP-104 delivered a prodigious 11-fold greater exposure of DON to tumor versus GI tissues. DRP-104 affected multiple metabolic pathways in tumor, including decreased glutamine flux into the TCA cycle. In efficacy studies, both DRP-104 and DON caused complete tumor regression; however, DRP-104 had a markedly improved tolerability profile. DRP-104's effect was CD8+ T cell dependent and resulted in robust immunologic memory. DRP-104 represents a first-in-class prodrug with differential metabolism in target versus toxicity tissue. DRP-104 is now in clinical trials under the FDA Fast Track designation.

• MeSH
• CD8-pozitivní T-lymfocyty metabolismus   MeSH
• diazooxonorleucin farmakologie   terapeutické užití   MeSH
• glutamin metabolismus   MeSH
• inhibitory enzymů terapeutické užití   MeSH
• lidé MeSH
• nádory * farmakoterapie   MeSH
• prekurzory léčiv * farmakologie   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

There are a number of clinically effective treatments for stress-associated psychiatric diseases, including major depressive disorder (MDD). Nonetheless, many patients exhibit resistance to first-line interventions calling for novel interventions based on pathological mechanisms. Accumulating evidence implicates altered glutamate signaling in MDD pathophysiology, suggesting that modulation of glutamate signaling cascades may offer novel therapeutic potential. Here we report that JHU-083, our recently developed prodrug of the glutaminase inhibitor 6-diazo-5-oxo-L-norleucine (DON) ameliorates social avoidance and anhedonia-like behaviors in mice subjected to chronic social defeat stress (CSDS). JHU-083 normalized CSDS-induced increases in glutaminase activity specifically in microglia-enriched CD11b+ cells isolated from the prefrontal cortex and hippocampus. JHU-083 treatment also reverses the CSDS-induced inflammatory activation of CD11b+ cells. These results support the importance of altered glutamate signaling in the behavioral abnormalities observed in the CSDS model, and identify glutaminase in microglia-enriched CD11b+ cells as a pharmacotherapeutic target implicated in the pathophysiology of stress-associated psychiatric conditions such as MDD.

• MeSH
• antigeny CD11b * MeSH
• chování zvířat účinky léků   MeSH
• deprese etiologie   prevence a kontrola   MeSH
• diazooxonorleucin * farmakologie   MeSH
• glutaminasa účinky léků   MeSH
• hipokampus účinky léků   imunologie   metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• prefrontální mozková kůra účinky léků   imunologie   metabolismus   MeSH
• prekurzory léčiv * farmakologie   MeSH
• psychický stres komplikace   MeSH
• signální transdukce MeSH
• zánět farmakoterapie   imunologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

6-Diazo-5-oxo-l-norleucine (DON) is a glutamine antagonist with robust anticancer efficacy; however, its therapeutic potential was hampered by its biodistribution and toxicity to normal tissues, specifically gastrointestinal (GI) tissues. To circumvent DON's toxicity, we synthesized a series of tumor-targeted DON prodrugs designed to circulate inert in plasma and preferentially activate over DON in tumor. Our best prodrug 6 (isopropyl 2-(6-acetamido-2-(adamantane-1-carboxamido)hexanamido)-6-diazo-5-oxohexanoate) showed stability in plasma, liver, and intestinal homogenates yet was readily cleaved to DON in P493B lymphoma cells, exhibiting a 55-fold enhanced tumor cell-to-plasma ratio versus that of DON and resulting in a dose-dependent inhibition of cell proliferation. Using carboxylesterase 1 knockout mice that were shown to mimic human prodrug metabolism, systemic administration of 6 delivered 11-fold higher DON exposure to tumor (target tissue; AUC0- t = 5.1 nmol h/g) versus GI tissues (toxicity tissue; AUC0- t = 0.45 nmol h/g). In summary, these studies describe the discovery of a glutamine antagonist prodrug that provides selective tumor exposure.

• MeSH
• acetylace MeSH
• antitumorózní látky aplikace a dávkování   MeSH
• diazooxonorleucin aplikace a dávkování   farmakokinetika   MeSH
• karboxylesterhydrolasy genetika   MeSH
• lidé MeSH
• lysin chemie   MeSH
• myši knockoutované MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• plocha pod křivkou MeSH
• prasata MeSH
• prekurzory léčiv chemie   MeSH
• systémy cílené aplikace léků * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Aberrant excitatory neurotransmission associated with overproduction of glutamate has been implicated in the development of HIV-associated neurocognitive disorders (HAND). The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON, 14) attenuates glutamate synthesis in HIV-infected microglia/macrophages, offering therapeutic potential for HAND. We show that 14 prevents manifestation of spatial memory deficits in chimeric EcoHIV-infected mice, a model of HAND. 14 is not clinically available, however, because its development was hampered by peripheral toxicities. We describe the synthesis of several substituted N-(pivaloyloxy)alkoxy-carbonyl prodrugs of 14 designed to circulate inert in plasma and be taken up and biotransformed to 14 in the brain. The lead prodrug, isopropyl 6-diazo-5-oxo-2-(((phenyl(pivaloyloxy)methoxy)carbonyl)amino)hexanoate (13d), was stable in swine and human plasma but liberated 14 in swine brain homogenate. When dosed systemically in swine, 13d provided a 15-fold enhanced CSF-to-plasma ratio and a 9-fold enhanced brain-to-plasma ratio relative to 14, opening a possible clinical path for the treatment of HAND.

• MeSH
• aminokapronáty aplikace a dávkování   chemická syntéza   farmakologie   MeSH
• azosloučeniny aplikace a dávkování   chemická syntéza   farmakologie   MeSH
• diazooxonorleucin aplikace a dávkování   farmakologie   MeSH
• glutaminasa antagonisté a inhibitory   MeSH
• HIV infekce komplikace   MeSH
• krev metabolismus   MeSH
• kyselina glutamová metabolismus   MeSH
• lidé MeSH
• mozek metabolismus   MeSH
• myši inbrední C57BL MeSH
• neurokognitivní poruchy farmakoterapie   etiologie   MeSH
• nootropní látky aplikace a dávkování   chemická syntéza   farmakologie   MeSH
• prasata MeSH
• prekurzory léčiv aplikace a dávkování   chemická syntéza   farmakologie   MeSH
• stabilita léku MeSH
• virová nálož účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Článek popisuje historii uvedení aprotininu do kardiochirurgické klinické praxe, zabývá se okolnostmi jeho stažení z celosvětového lékového trhu na základě výsledků studie BART a jeho nedávným opětovným schválením v některých státech.

The article describes the history of introducing aprotinin into cardio-surgical clinical practice and deals with the circumstances based on the results of the BART study leading to its withdrawal from the global pharmaceutical market and with its recent re-authorization in some countries.

• Klíčová slova
• studie BART,
• MeSH
• antifibrinolytika škodlivé účinky   terapeutické užití   MeSH
• aprotinin * farmakologie   škodlivé účinky   terapeutické užití   MeSH
• infarkt myokardu chemicky indukované   MeSH
• kardiochirurgické výkony * MeSH
• krvácení při operaci prevence a kontrola   MeSH
• kyselina 6-aminokapronová terapeutické užití   MeSH
• kyselina tranexamová terapeutické užití   MeSH
• lidé MeSH
• multicentrické studie jako téma MeSH
• pooperační krvácení prevence a kontrola   MeSH
• randomizované kontrolované studie jako téma MeSH
• renální insuficience chemicky indukované   MeSH
• schvalování léčiv MeSH
• stažení léku z trhu z bezpečnostních důvodů * MeSH
• Check Tag
• lidé MeSH

The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON, 1) has shown robust anticancer efficacy in preclinical and clinical studies, but its development was halted due to marked systemic toxicities. Herein we demonstrate that DON inhibits glutamine metabolism and provides antitumor efficacy in a murine model of glioblastoma, although toxicity was observed. To enhance DON's therapeutic index, we utilized a prodrug strategy to increase its brain delivery and limit systemic exposure. Unexpectedly, simple alkyl ester-based prodrugs were ineffective due to chemical instability cyclizing to form a unique diazo-imine. However, masking both DON's amine and carboxylate functionalities imparted sufficient chemical stability for biological testing. While these dual moiety prodrugs exhibited rapid metabolism in mouse plasma, several provided excellent stability in monkey and human plasma. The most stable compound (5c, methyl-POM-DON-isopropyl-ester) was evaluated in monkeys, where it achieved 10-fold enhanced cerebrospinal fluid to plasma ratio versus DON. This strategy may provide a path to DON utilization in glioblastoma multiforme patients.

• MeSH
• antimetabolity antitumorózní terapeutické užití   MeSH
• diazooxonorleucin terapeutické užití   MeSH
• glioblastom farmakoterapie   metabolismus   MeSH
• glutamin metabolismus   MeSH
• Haplorrhini MeSH
• lidé MeSH
• myši nahé MeSH
• myši MeSH
• nádory mozku farmakoterapie   metabolismus   MeSH
• prekurzory léčiv farmakokinetika   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Skin penetration enhancers are compounds used to facilitate the transdermal delivery of drugs that are otherwise not sufficiently permeable. Through a synthetic route implementing two series of esters, we generated transdermal penetration enhancers by a multi-step reaction with substituted 6-aminohexanoic acid. We present the synthesis of all newly prepared compounds here with structural confirmation accomplished by (1)H NMR, (13)C NMR, IR and mass spectroscopy (MS). The lipophilicity (logk) of all compounds was determined via RP-HPLC and their hydrophobicity (logP/ClogP) was also calculated using two commercially available programs. Ab initio calculations of geometry and molecular dynamic simulations were employed to investigate the 3-dimensional structures of selected compounds. The transdermal penetration-enhancing activity of all the synthesized esters were examined in vitro and demonstrated higher enhancement ratios than oleic acid. Compounds 2e (C(10) ester chain) and 2f (C(11) ester chain) exhibited the highest enhancement ratios. It can be concluded that the series non-substituted at the C((2)) position by a ω-lactam ring showed significantly higher activity than those with azepan-2-one. None of the prepared compounds penetrated through the skin. All of the investigated agents demonstrated minimal anti-proliferative activity using the SK-N-MC neuroepithelioma cell line (IC(50)>6.25μM), suggesting these analogs would have a low cytotoxic profile when administered in vivo as chemical penetration enhancers. The correlation between the chemical structure of the studied compounds and their lipophilicity is discussed in regards to transdermal penetration-enhancing activity.

• MeSH
• antitumorózní látky chemická syntéza   chemie   farmakologie   MeSH
• aplikace lokální MeSH
• hydrofobní a hydrofilní interakce MeSH
• kapronáty chemická syntéza   chemie   farmakologie   MeSH
• kožní absorpce MeSH
• kůže účinky léků   MeSH
• kyselina 6-aminokapronová chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• prasata MeSH
• pyrrolidiny chemická syntéza   chemie   farmakologie   MeSH
• simulace molekulární dynamiky MeSH
• stereoizomerie MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Transdermal permeation enhancers are compounds that temporarily increase drug flux through the skin by interacting with constituents of the stratum corneum. Transkarbam 12 (T12) is a highly active, broad-spectrum, biodegradable enhancer with low toxicity and low dermal irritation. We show here that T12 acts by a dual mechanism of action. The first part of this activity is associated with its ammonium carbamate polar head as shown by its pH-dependent effects on the permeation of two model drugs. Once this ammonium carbamate penetrates into the stratum corneum intercellular lipids, it rapidly decomposes releasing two molecules of protonated dodecyl 6-aminohexanoate (DDEAC) and carbon dioxide. This was observed by thermogravimetric analysis and infrared spectroscopy. This step of T12 action influences drug permeation through lipidic pathways, not through the aqueous pores (polar pathway) as shown by its effects on various model drugs and electrical impedance. Consequently, protonated DDEAC released in the stratum corneum is also an active enhancer. It broadens the scope of T12 action since it is also able to increase permeation of hydrophilic drugs that prefer the pore pathway. Thus, this dual effect of T12 is likely responsible for its favorable properties, which make it a good candidate for prospective clinical use.

• MeSH
• adjuvancia farmaceutická chemie   metabolismus   farmakologie   MeSH
• aminokapronáty MeSH
• aplikace kožní MeSH
• elektrická impedance MeSH
• epidermis chemie   MeSH
• fyziologie kůže účinky léků   MeSH
• hydrokortison aplikace a dávkování   metabolismus   MeSH
• karbamáty chemie   metabolismus   farmakologie   MeSH
• koncentrace vodíkových iontů MeSH
• kožní absorpce účinky léků   MeSH
• kůže účinky léků   metabolismus   MeSH
• kyselina 6-aminokapronová chemie   metabolismus   farmakologie   MeSH
• kyselina palmitová chemie   MeSH
• lipidy chemie   izolace a purifikace   MeSH
• oxid uhličitý chemie   metabolismus   MeSH
• permeabilita účinky léků   MeSH
• spektrofotometrie infračervená MeSH
• Sus scrofa MeSH
• termogravimetrie MeSH
• theofylin aplikace a dávkování   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH