Neutral sphingomyelinase 2 (nSMase2) has gained increasing attention as a therapeutic target to regulate ceramide production in various disease conditions. Phenyl (R)-(1-(3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl)-pyrrolidin-3-yl)carbamate (PDDC) is a submicromolar nSMase2 inhibitor and has been widely used to study the pharmacological effects of nSMase2 inhibition. Through screening of compounds containing a bicyclic 5-6 fused ring, larotrectinib containing a pyrazolo[1,5-a]pyrimidine ring was identified as a low micromolar inhibitor of nSMase2. This prompted us to investigate the pyrazolo[1,5-a]pyrimidin-3-amine ring as a novel scaffold to replace the imidazo[1,2-b]pyridazine-8-amine ring of PDDC. A series of molecules containing a pyrazolo[1,5-a]pyrimidin-3-amine ring were synthesized and tested for their ability to inhibit human nSMase2. Several compounds exhibited nSMase2 inhibitory potency superior to that of PDDC. Among these, N,N-dimethyl-5-morpholinopyrazolo[1,5-a]pyrimidin-3-amine (11j) was found to be metabolically stable in liver microsomes and orally available with a favorable brain-to-plasma ratio, demonstrating the potential of pyrazolo[1,5-a]pyrimidine ring as an effective scaffold for nSMase2 inhibition.

• MeSH
• aminy * MeSH
• ceramidy MeSH
• lidé MeSH
• pyrimidiny farmakologie   MeSH
• sfingomyelinfosfodiesterasa * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Hyperprogressive disease (HPD) is a new phenomenon that has emerged in the immunotherapy era. HPD is defined as a rapid tumour growth with detrimental effect on the patient condition and disease course. The management and treatment following HPD is not defined. We present here the case report of patient with HPD and review of the literature on putative mechanisms of HPD and following disease management. METHODS AND RESULTS: A 60-year old male patient with metastatic melanoma was indicated for systemic treatment with anti-programmed cell death (PD)-1 antibody. Rapid tumour growth and detrimental effect on the patient general condition after administration of a single dose of anti-PD-1 antibody met the criteria of HPD. The patient underwent the second line taxane-based chemotherapy with good tolerance and disease stabilization. The third line treatment with anti- cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody ipilimumab was well tolerated and resulted in partial response. Re-challenge with anti-CTLA-4 antibody was feasible, but only with a modest clinical effect. CONCLUSION: Prompt recognition of HPD and administration of salvage chemotherapy with taxane-based regimens may be crucial. HPD is rarely observed with ipilimumab treatment. Administration of ipilimumab as well as an ipilimumab re-challenge are feasible after HPD on anti-PD-1 antibodies. Investigation of new predictive biomarkers of HPD is warranted as well as new agents that potentiate the immune response in patients affected with this insidious complication.

• MeSH
• ipilimumab terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• melanom * farmakoterapie   patologie   MeSH
• nivolumab * škodlivé účinky   MeSH
• progrese nemoci MeSH
• taxoidy terapeutické užití   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH
• přehledy MeSH

Purine nucleoside phosphorylase (PNP) is a well-known molecular target with potential therapeutic applications in the treatment of T-cell malignancies and/or bacterial/parasitic infections. Here, we report the design, development of synthetic methodology, and biological evaluation of a series of 30 novel PNP inhibitors based on acyclic nucleoside phosphonates bearing a 9-deazahypoxanthine nucleobase. The strongest inhibitors exhibited IC50 values as low as 19 nM (human PNP) and 4 nM (Mycobacterium tuberculosis (Mt) PNP) and highly selective cytotoxicity toward various T-lymphoblastic cell lines with CC50 values as low as 9 nM. No cytotoxic effect was observed on other cancer cell lines (HeLa S3, HL60, HepG2) or primary PBMCs for up to 10 μM. We report the first example of the PNP inhibitor exhibiting over 60-fold selectivity for the pathogenic enzyme (MtPNP) over hPNP. The results are supported by a crystallographic study of eight enzyme-inhibitor complexes and by ADMET profiling in vitro and in vivo.

• MeSH
• inhibitory enzymů * chemie   MeSH
• krystalografie MeSH
• lidé MeSH
• purinnukleosidfosforylasa * metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

A series of novel acyclic nucleoside phosphonates (ANPs) was synthesized as potential adenylate cyclase inhibitors, where the adenine nucleobase of adefovir (PMEA) was replaced with a 5-substituted 2-aminothiazole moiety. The design was based on the structure of MB05032, a potent and selective inhibitor of fructose 1,6-bisphosphatase and a good mimic of adenosine monophosphate (AMP). From the series of eighteen novel ANPs, which were prepared as phosphoroamidate prodrugs, fourteen compounds were potent (single digit micromolar or submicromolar) inhibitors of Bordetella pertussis adenylate cyclase toxin (ACT), mostly without observed cytotoxicity in J774A.1 macrophage cells. Selected phosphono diphosphates (nucleoside triphosphate analogues) were potent inhibitors of ACT (IC50 as low as 37 nM) and B. anthracis edema factor (IC50 as low as 235 nM) in enzymatic assays. Furthermore, several ANPs were found to be selective mammalian AC1 inhibitors in HEK293 cell-based assays (although with some associated cytotoxicity) and one compound exhibited selective inhibition of mammalian AC2 (only 12% of remaining adenylate cyclase activity) but no observed cytotoxicity. The mammalian AC1 inhibitors may represent potential leads in development of agents for treatment of human inflammatory and neuropathic pain.

• MeSH
• adenylátcyklasový toxin antagonisté a inhibitory   metabolismus   MeSH
• antibakteriální látky chemická syntéza   chemie   farmakologie   MeSH
• Bacillus anthracis účinky léků   MeSH
• Bordetella pertussis účinky léků   enzymologie   MeSH
• buněčné linie MeSH
• inhibitory adenylylcyklasy chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• molekulární struktura MeSH
• myši MeSH
• neuralgie farmakoterapie   MeSH
• organofosfonáty chemie   farmakologie   MeSH
• thiazoly chemie   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) is a recognized target for antimalarial chemotherapeutics. It synthesises all of the 6-oxopurine nucleoside monophosphates, IMP, GMP and XMP needed by the malarial parasite, Plasmodium falciparum (Pf). PfHGXPRT is also indirectly responsible for the synthesis of the adenosine monophosphate, AMP. The acyclic nucleoside phosphonates (ANPs) are a class of PfHGXPRT inhibitors. Prodrugs of these compounds are able to arrest the growth of Pf in cell culture. In the search for new inhibitors of PfHGXPRT, a series of sulfur containing ANPs (thia-ANPs) has been designed and synthesized. These compounds are based on the structure of 2-(phosphonoethoxy)ethylguanine (PEEG) and PEEHx which consist of a purine base (i.e. guanine or hypoxanthine) linked to a phosphonate group by five atoms i.e. four carbons and one oxygen. Here, PEEG and PEEHx were modified by substituting a sulfide, sulfoxide or a sulfone bridge for the oxygen atom in the linker. The effect of these substitutions on the Ki values for human HGPRT and PfHGXPRT was investigated and showed that most of the thia-ANPs distinctively favour PfHGXPRT. For example, the thia-analogue of PEEHx has a Ki value of 0.2 μM for PfHGXPRT, a value 25-fold lower than for the human counterpart. Prodrugs of these compounds have IC50 values in the 4-6 μM range in antimalarial cell-based assays, making them attractive compounds for further development as antimalarial drug leads.

• MeSH
• antimalarika chemická syntéza   farmakologie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• nukleosidy chemická syntéza   farmakologie   MeSH
• organofosfonáty chemická syntéza   farmakologie   MeSH
• oxidace-redukce MeSH
• pentosyltransferasy antagonisté a inhibitory   MeSH
• Plasmodium falciparum účinky léků   enzymologie   MeSH
• prekurzory léčiv chemická syntéza   farmakologie   MeSH
• sulfidy chemie   MeSH
• sulfony chemie   MeSH
• sulfoxidy chemie   MeSH
• termodynamika MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

A series of 13 acyclic nucleoside phosphonates (ANPs) as bisamidate prodrugs was prepared. Five compounds were found to be non-cytotoxic and selective inhibitors of Bordetella pertussis adenylate cyclase toxin (ACT) in J774A.1 macrophage cell-based assays. The 8-aza-7-deazapurine derivative of adefovir (PMEA) was found to be the most potent ACT inhibitor in the series (IC50 =16 nm) with substantial selectivity over mammalian adenylate cyclases (mACs). AC inhibitory properties of the most potent analogues were confirmed by direct evaluation of the corresponding phosphonodiphosphates in cell-free assays and were found to be potent inhibitors of both ACT and edema factor (EF) from Bacillus anthracis (IC50 values ranging from 0.5 to 21 nm). Moreover, 7-halo-7-deazapurine analogues of PMEA were discovered to be potent and selective mammalian AC1 inhibitors (no inhibition of AC2 and AC5) with IC50 values ranging from 4.1 to 5.6 μm in HEK293 cell-based assays.

• MeSH
• adenin analogy a deriváty   chemická syntéza   chemie   farmakologie   MeSH
• adenylátcyklasy metabolismus   MeSH
• Bacillus anthracis enzymologie   MeSH
• Bordetella pertussis enzymologie   MeSH
• inhibitory enzymů chemická syntéza   chemie   farmakologie   MeSH
• molekulární struktura MeSH
• organofosfonáty chemická syntéza   chemie   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Inhibition of Bordetella pertussis adenylate cyclase toxin (ACT) and Bacillus anthracis edema factor (EF), key virulence factors with adenylate cyclase activity, represents a potential method for treating or preventing toxemia related to whooping cough and anthrax, respectively. Novel α-branched acyclic nucleoside phosphonates (ANPs) having a hemiaminal ether moiety were synthesized as potential inhibitors of bacterial adenylate cyclases. ANPs prepared as bisamidates were not cytotoxic, but did not exhibit any profound activity (IC50 >10 μm) toward ACT in J774A.1 macrophages. The apparent lack of activity of the bisamidates is speculated to be due to the inefficient formation of the biologically active species (ANPpp) in the cells. Conversely, two 5-haloanthraniloyl-substituted ANPs in the form of diphosphates were shown to be potent ACT and EF inhibitors with IC50 values ranging from 55 to 362 nm.

• MeSH
• adenylátcyklasový toxin antagonisté a inhibitory   MeSH
• antigeny bakteriální MeSH
• bakteriální proteiny antagonisté a inhibitory   MeSH
• bakteriální toxiny antagonisté a inhibitory   MeSH
• buněčné linie MeSH
• inhibitory adenylylcyklasy chemie   farmakologie   MeSH
• konformace proteinů MeSH
• lidé MeSH
• makrofágy cytologie   účinky léků   MeSH
• nukleosidy chemie   farmakologie   MeSH
• organofosfonáty chemie   farmakologie   MeSH
• simulace molekulového dockingu MeSH
• vazba proteinů MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Bordetella pertussis adenylate cyclase toxin (ACT) and Bacillus anthracis edema factor (EF) are key virulence factors with adenylate cyclase (AC) activity that substantially contribute to the pathogenesis of whooping cough and anthrax, respectively. There is an urgent need to develop potent and selective inhibitors of bacterial ACs with prospects for the development of potential antibacterial therapeutics and to study their molecular interactions with the target enzymes. Novel fluorescent 5-chloroanthraniloyl-substituted acyclic nucleoside phosphonates (Cl-ANT-ANPs) were designed and synthesized in the form of their diphosphates (Cl-ANT-ANPpp) as competitive ACT and EF inhibitors with sub-micromolar potency (IC50 values: 11-622 nm). Fluorescence experiments indicated that Cl-ANT-ANPpp analogues bind to the ACT active site, and docking studies suggested that the Cl-ANT group interacts with Phe306 and Leu60. Interestingly, the increase in direct fluorescence with Cl-ANT-ANPpp having an ester linker was strictly calmodulin (CaM)-dependent, whereas Cl-ANT-ANPpp analogues with an amide linker, upon binding to ACT, increased the fluorescence even in the absence of CaM. Such a dependence of binding on structural modification could be exploited in the future design of potent inhibitors of bacterial ACs. Furthermore, one Cl-ANT-ANP in the form of a bisamidate prodrug was able to inhibit B. pertussis ACT activity in macrophage cells with IC50 =12 μm.

• MeSH
• adenylátcyklasy metabolismus   MeSH
• Bordetella pertussis enzymologie   MeSH
• fluorescenční barviva chemická syntéza   chemie   farmakologie   MeSH
• inhibitory adenylylcyklasy chemická syntéza   chemie   farmakologie   MeSH
• makrofágy účinky léků   MeSH
• molekulární struktura MeSH
• myši MeSH
• nukleosidy chemická syntéza   chemie   farmakologie   MeSH
• organofosfonáty chemická syntéza   chemie   farmakologie   MeSH
• racionální návrh léčiv * MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• licence lékařská zákonodárství a právo   MeSH
• lidé MeSH
• nesprávné profesionální chování klasifikace   zákonodárství a právo   MeSH
• poskytování zdravotní péče zákonodárství a právo   MeSH
• transport pacientů organizace a řízení   zákonodárství a právo   MeSH
• zákonodárství lékařské normy   trendy   MeSH
• zapojení pacienta zákonodárství a právo   MeSH
• zdravotnické služby zákonodárství a právo   MeSH
• Check Tag
• lidé MeSH

• MeSH
• dostupnost zdravotnických služeb normy   organizace a řízení   MeSH
• poskytování zdravotní péče organizace a řízení   zákonodárství a právo   MeSH
• urgentní služby nemocnice organizace a řízení   zákonodárství a právo   MeSH
• uzavření zdravotnického zařízení normy   statistika a číselné údaje   zákonodárství a právo   MeSH
• zdravotní péče - kvalita, dosažitelnost a hodnocení MeSH