Aderamastat (FP-025) is a small molecule, selective matrix metalloproteinase (MMP)-12 inhibitor, under development for respiratory conditions which may include chronic inflammatory airway diseases and pulmonary fibrosis. To support evaluation of the pharmacokinetic parameters of Aderamastat in humans, we developed and validated a high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS) analytical method for the quantification of Aderamastat in human plasma. This assay was validated in compliance with the Food and Drug Administration (FDA) Good Laboratory Practice Regulations (GLP) and European Medicines Agency (EMA) guidelines. K2EDTA human plasma samples were spiked with internal standard, processed by liquid-liquid extraction, and analyzed using reversed-phase HPLC with Turbo Ion Spray® MS/MS detection. Separation was done using a chromatographic gradient on 5 µm C6-Phenyl 110 Å, 50*2 mm analytical column at a temperature of 35 °C. The LC-MS/MS bioanalytical method, developed by QPS Taiwan to determine the concentration of Aderamastat in K2EDTA human plasma, was successfully validated with respect to linearity, sensitivity, accuracy, precision, dilution, selectivity, hemolyzed plasma, lipemic plasma, batch size, recovery, matrix effect, and carry-over. These data indicate that the method for determination of Aderamastat concentrations in human K2EDTA plasma can be used in pharmacokinetics studies and subsequent clinical trials with Aderamastat. Authors declare that, this novel data is not published and not under consideration for publication by another journal than this journal. All data will be made available on request.

• Klíčová slova
• Aderamastat, Bioanalysis Assay, FP-025, LC-MS/MS, Matrix Metalloproteinase (MMP)-12 inhibitor, Validation,
• MeSH
• adamantan analogy a deriváty   krev   farmakokinetika   chemie   MeSH
• chromatografie kapalinová metody   MeSH
• EDTA * chemie   krev   farmakokinetika   MeSH
• kapalinová chromatografie-hmotnostní spektrometrie MeSH
• lidé MeSH
• limita detekce MeSH
• lineární modely MeSH
• reprodukovatelnost výsledků MeSH
• stabilita léku MeSH
• tandemová hmotnostní spektrometrie * metody   MeSH
• vysokoúčinná kapalinová chromatografie metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adamantan MeSH
• EDTA * MeSH

Cyclin-dependent kinases (CDKs) play an important role in the cell-division cycle. Synthetic inhibitors of CDKs are based on 2,6,9-trisubstituted purines and are developed as potential anticancer drugs; however, they have low solubility in water. In this study, we proved that the pharmaco-chemical properties of purine-based inhibitors can be improved by appropriate substitution with the adamantane moiety. We prepared ten new purine derivatives with adamantane skeletons that were linked at position 6 using phenylene spacers of variable geometry and polarity. We demonstrated that the adamantane skeleton does not compromise the biological activity, and some of the new purines displayed even higher inhibition activity towards CDK2/cyclin E than the parental compounds. These findings were supported by a docking study, which showed an adamantane scaffold inside the binding pocket participating in the complex stabilisation with non-polar interactions. In addition, we demonstrated that β-cyclodextrin (CD) increases the drug's solubility in water, although this is at the cost of reducing the biochemical and cellular effect. Most likely, the drug concentration, which is necessary for target engagement, was decreased by competitive drug binding within the complex with β-CD.

• Klíčová slova
• 2,6,9-trisubstituted purine, adamantane, cyclin-dependent kinase, cytotoxicity, molecular docking, β-cyclodextrin,
• MeSH
• adamantan chemie   MeSH
• beta-cyklodextriny chemie   MeSH
• buňky K562 MeSH
• cyklin-dependentní kinasa 2 antagonisté a inhibitory   MeSH
• inhibitory proteinkinas farmakologie   MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• protinádorové látky chemie   farmakologie   MeSH
• puriny chemie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adamantan MeSH
• beta-cyklodextriny MeSH
• CDK2 protein, human MeSH Prohlížeč
• cyklin-dependentní kinasa 2 MeSH
• inhibitory proteinkinas MeSH
• protinádorové látky MeSH
• puriny MeSH

Multi-orthogonal molecular scaffolds can be applied as core structures of bioactive compounds. Here, we prepared four tri-orthogonal scaffolds based on adamantane or proline skeletons. The scaffolds were used for the solid-phase synthesis of model insulin mimetics bearing two different peptides on the scaffolds. We found that adamantane-derived compounds bind to the insulin receptor more effectively (Kd value of 0.5 μM) than proline-derived compounds (Kd values of 15-38 μM) bearing the same peptides. Molecular dynamics simulations suggest that spacers between peptides and central scaffolds can provide greater flexibility that can contribute to increased binding affinity. Molecular modeling showed possible binding modes of mimetics to the insulin receptor. Our data show that the structure of the central scaffold and flexibility of attached peptides in this type of compound are important and that different scaffolds should be considered when designing peptide hormone mimetics.

• Klíčová slova
• Hormone binding, Insulin receptor, Molecular dynamics, Peptidomimetics, Scaffold, Solid-phase peptide synthesis,
• MeSH
• adamantan chemie   MeSH
• inzulin analogy a deriváty   chemická syntéza   metabolismus   MeSH
• kinetika MeSH
• krysa rodu Rattus MeSH
• kvarterní struktura proteinů MeSH
• lidé MeSH
• prolin chemie   MeSH
• receptor inzulinu chemie   metabolismus   MeSH
• simulace molekulární dynamiky MeSH
• stabilita proteinů MeSH
• stereoizomerie MeSH
• techniky syntézy na pevné fázi MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adamantan MeSH
• inzulin MeSH
• prolin MeSH
• receptor inzulinu MeSH

A series of nineteen amino acid analogues of amantadine (Amt) and rimantadine (Rim) were synthesized and their antiviral activity was evaluated against influenza virus A (H3N2). Among these analogues, the conjugation of rimantadine with glycine illustrated high antiviral activity combined with low cytotoxicity. Moreover, this compound presented a profoundly high stability after in vitro incubation in human plasma for 24 h. Its thermal stability was established using differential and gravimetric thermal analysis. The crystal structure of glycyl-rimantadine revealed that it crystallizes in the orthorhombic Pbca space group. The structure-activity relationship for this class of compounds was established, with CoMFA (Comparative Molecular Field Analysis) 3D-Quantitative Structure Activity Relationships (3D-QSAR) studies predicting the activities of synthetic molecules. In addition, molecular docking studies were conducted, revealing the structural requirements for the activity of the synthetic molecules.

• Klíčová slova
• 3D-QSAR, LC–MS/MS., X-Ray crystallography, adamantane derivatives, amino acids, mass spectrometry, molecular docking, plasma stability,
• MeSH
• adamantan analogy a deriváty   chemická syntéza   chemie   farmakologie   MeSH
• antivirové látky chemická syntéza   chemie   farmakologie   MeSH
• buněčná smrt účinky léků   MeSH
• buňky MDCK MeSH
• diferenční termická analýza MeSH
• krystalografie rentgenová MeSH
• kvantitativní vztahy mezi strukturou a aktivitou * MeSH
• lidé MeSH
• metoda nejmenších čtverců MeSH
• molekulární konformace MeSH
• Orthomyxoviridae účinky léků   MeSH
• počítačová simulace * MeSH
• proteinové domény MeSH
• proteiny virové matrix chemie   MeSH
• psi MeSH
• rimantadin krev   chemie   MeSH
• simulace molekulového dockingu MeSH
• stabilita léku MeSH
• teplota MeSH
• vazebná místa MeSH
• vodíková vazba MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• psi MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adamantan MeSH
• antivirové látky MeSH
• M2 protein, Influenza A virus MeSH Prohlížeč
• proteiny virové matrix MeSH
• rimantadin MeSH

BACKGROUND AND PURPOSE: Results regarding protective effects of dipeptidyl peptidase 4 (DPP4) inhibitors in renal ischaemia-reperfusion injury (IRI) are conflicting. Here we have compared structurally unrelated DPP4 inhibitors in a model of renal IRI. EXPERIMENTAL APPROACH: IRI was induced in uninephrectomized male rats by renal artery clamping for 30 min. The sham group was uninephrectomized but not subjected to IRI. DPP4 inhibitors or vehicle were given p.o. once daily on three consecutive days prior to IRI: linagliptin (1.5 mg·kg-1 ·day-1 ), vildagliptin (8 mg·kg-1 ·day-1 ) and sitagliptin (30 mg·kg-1 ·day-1 ). An additional group received sitagliptin until study end (before IRI: 30 mg·kg-1 ·day-1 ; after IRI: 15 mg·kg-1 ·day-1 ). KEY RESULTS: Plasma-active glucagon-like peptide type 1 (GLP-1) increased threefold to fourfold in all DPP4 inhibitor groups 24 h after IRI. Plasma cystatin C, a marker of GFR, peaked 48 h after IRI. Compared with the placebo group, DPP4 inhibition did not reduce increased plasma cystatin C levels. DPP4 inhibitors ameliorated histopathologically assessed tubular damage with varying degrees of drug-specific efficacies. Renal osteopontin expression was uniformly reduced by all DPP4 inhibitors. IRI-related increased renal cytokine expression was not decreased by DPP4 inhibition. Renal DPP4 activity at study end was significantly inhibited in the linagliptin group, but only numerically reduced in the prolonged/dose-adjusted sitagliptin group. Active GLP-1 plasma levels at study end were increased only in the prolonged/dose-adjusted sitagliptin treatment group. CONCLUSIONS AND IMPLICATIONS: In rats with renal IRI, DPP4 inhibition did not alter plasma cystatin C, a marker of glomerular function, but may protect against tubular damage.

• MeSH
• adamantan aplikace a dávkování   analogy a deriváty   chemie   farmakologie   MeSH
• dipeptidylpeptidasa 4 metabolismus   MeSH
• inhibitory dipeptidylpeptidasy 4 aplikace a dávkování   chemie   farmakologie   MeSH
• krysa rodu Rattus MeSH
• ledviny účinky léků   metabolismus   patologie   MeSH
• linagliptin aplikace a dávkování   chemie   farmakologie   MeSH
• molekulární struktura MeSH
• nitrily aplikace a dávkování   chemie   farmakologie   MeSH
• potkani Wistar MeSH
• pyrrolidiny aplikace a dávkování   chemie   farmakologie   MeSH
• reperfuzní poškození farmakoterapie   metabolismus   patologie   MeSH
• sitagliptin fosfát aplikace a dávkování   chemie   farmakologie   MeSH
• vildagliptin MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• adamantan MeSH
• dipeptidylpeptidasa 4 MeSH
• DPP4 protein, rat MeSH Prohlížeč
• inhibitory dipeptidylpeptidasy 4 MeSH
• linagliptin MeSH
• nitrily MeSH
• pyrrolidiny MeSH
• sitagliptin fosfát MeSH
• vildagliptin MeSH

Bisimidazolium salts with one central biphenyl binding site and two terminal adamantyl binding sites form water-soluble binary or ternary aggregates with cucurbit[7]uril (CB7) and β-cyclodextrin (β-CD) with rotaxane and pseudorotaxane architectures. The observed arrangements result from cooperation of the supramolecular stopper binding strength and steric barriers against free slippage of the CB7 and β-CD host molecules over the bisimidazolium guest axle.

• Klíčová slova
• cucurbituril, cyclodextrins, host-guest systems, rotaxanes, supramolecular chemistry,
• MeSH
• adamantan analogy a deriváty   chemie   MeSH
• beta-cyklodextriny chemie   MeSH
• bifenylové sloučeniny chemie   MeSH
• imidazoly chemie   MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• rotaxany chemie   MeSH
• soli chemie   MeSH
• vazebná místa MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adamantan MeSH
• beta-cyklodextriny MeSH
• betadex MeSH Prohlížeč
• bifenylové sloučeniny MeSH
• imidazoly MeSH
• rotaxany MeSH
• soli MeSH

To investigate structure-function relationships of cytochromes P450 (CYP), 3-azidiamantane was employed for photoaffinity labeling of rabbit microsomal CYP2B4. Four diamantane labeled tryptic fragments were identified by mass spectrometry and sequencing: peptide I (Leu359-Lys373), peptide II (Leu30-Arg48), peptide III (Phe127-Arg140), and peptide IV (Arg434-Arg443). Their positions were projected into CYP2B4 model structures and compared with substrate binding sites, proposed by docking of diamantane. We identified novel binding regions outside the active site of CYP2B4. One of them, defined with diamantane modified Arg133, marks a possible entrance to the active site from the heme proximal face. In addition to crystal structures of CYP2B4 chimeras and molecular dynamics simulations, our data of photoaffinity labeling of the full CYP2B4 molecule provide further insight into functional and structural aspects of substrate binding.

• MeSH
• adamantan analogy a deriváty   chemie   MeSH
• aromatické hydroxylasy chemie   ultrastruktura   MeSH
• chemické modely * MeSH
• fluorescenční mikroskopie metody   MeSH
• fotochemie metody   MeSH
• konformace proteinů MeSH
• molekulární modely * MeSH
• počítačová simulace MeSH
• rodina 2 cytochromů P450 MeSH
• substrátová specifita MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 3-azidiamantane MeSH Prohlížeč
• adamantan MeSH
• aromatické hydroxylasy MeSH
• cytochrome P-450 CYP2B4 (rabbit) MeSH Prohlížeč
• rodina 2 cytochromů P450 MeSH

The structure of sinaicinone, isolated from the aerial parts of the Egyptian medicinal plant Hypericum sinaicum, has been elucidated by means of spectroscopic data such as UV, IR, MS, 1D and 2D NMR spectra, and chemical degradation. It is a complex adamantanyl derivative with a unique skeleton and oxygenated side chains.

• MeSH
• adamantan analogy a deriváty   chemie   izolace a purifikace   MeSH
• léčivé rostliny chemie   MeSH
• molekulární struktura MeSH
• nadzemní části rostlin chemie   MeSH
• třezalka chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Egypt MeSH
• Názvy látek
• adamantan MeSH
• sinaicinone MeSH Prohlížeč

The series of diamondoids: adamantane, diamantane, triamantane, 2-isopropenyl-2-methyladamantane and 3-isopropenyl-3-methyldiamantane (3-IPMDIA), were employed to elucidate the molecular basis of their interaction with the active site of cytochromes P450 (CYP) of a 2B subfamily. These potent inhibitors of CYP2B enzymes were docked into the homology model of CYP2B4. Apparent dissociation constants calculated for the complexes of CYP2B4 with docked diamandoids agreed closely with the experimental data showing inhibition potency of the compounds and their binding affinity to CYP2B4. Superimposed structures of docked diamondoids mapped binding site residues. As they are mainly non-polar residues, the hydrophobicity plays the major role in the binding of diamondoids. Overlapping structure of diamondoids defined an elliptical binding cavity (5.9A inner diameter, 7.9A length) forming an angle of approximately 43 degrees with the heme plane. CYP2B specific diamondoids, namely 3-IPMDIA, showing the highest binding affinity, should be considered for a potential clinical use.

• MeSH
• adamantan analogy a deriváty   chemie   metabolismus   farmakologie   MeSH
• aromatické hydroxylasy antagonisté a inhibitory   genetika   metabolismus   MeSH
• cytochrom P-450 CYP2B1 antagonisté a inhibitory   genetika   metabolismus   MeSH
• hydrofobní a hydrofilní interakce MeSH
• inhibitory enzymů chemie   metabolismus   farmakologie   MeSH
• jaterní mikrozomy enzymologie   MeSH
• králíci MeSH
• krysa rodu Rattus MeSH
• molekulární struktura MeSH
• potkani Wistar MeSH
• rodina 2 cytochromů P450 MeSH
• vazebná místa MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• 2-isopropenyl-2-methyladamantane MeSH Prohlížeč
• 3-isopropenyl-3-methyldiamantane MeSH Prohlížeč
• adamantan MeSH
• aromatické hydroxylasy MeSH
• cytochrom P-450 CYP2B1 MeSH
• cytochrome P-450 CYP2B4 (rabbit) MeSH Prohlížeč
• inhibitory enzymů MeSH
• rodina 2 cytochromů P450 MeSH

Hydrocarbone diamantane has been shown to be a specific substrate with a high affinity for the binding site of PB-inducible cytochrome P-450 2B1 (Hodek et al. 1988). Using a difference spectroscopy approach, a battery of diamantane analogues and diamantane oxygen containing derivatives were examined for their interaction with P-450 2B1 active site. Of the compounds (diamantane and its analogues, adamantane and triamantane) tested, diamantane had the lowest value of a spectral dissociation constant Ks = 0.5 mumol/l, indicating that diamantane was accommodated well to the cytochrome P-450 2B1, hence values of 0.46 nm and 0.66 nm for the width and length of the diamantane molecule, respectively, were used to describe of the dimensions the cytochrome P-450 binding site. Adamantane (Ks = 1.3 mumol/l) is relatively small and thus it binds loosely whereas triamantane (Ks = 4.3 mumol/l) is bulky enough to fit the binding site. This conclusion has been confirmed by spectral competition experiments as well as metabolic studies. Of all oxygen containing derivatives diamantane 1,6-dicarboxylic acid dimethylester only exhibited a pronounced ligand interaction with cytochrome P-450. Using molecular dimensions of this derivative the distance of 0.56 nm from the heme iron to the center of the substrate binding site was estimated.

• MeSH
• adamantan analogy a deriváty   chemie   metabolismus   MeSH
• aminopyrin metabolismus   MeSH
• aromatické hydroxylasy * MeSH
• biofyzika MeSH
• biofyzikální jevy MeSH
• jaterní mikrozomy enzymologie   MeSH
• kinetika MeSH
• kompetitivní vazba MeSH
• krysa rodu Rattus MeSH
• molekulární struktura MeSH
• potkani Wistar MeSH
• steroidhydroxylasy chemie   metabolismus   MeSH
• systém (enzymů) cytochromů P-450 chemie   metabolismus   MeSH
• techniky in vitro MeSH
• vazebná místa MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adamantan MeSH
• aminopyrin MeSH
• aromatické hydroxylasy * MeSH
• steroid 16-beta-hydroxylase MeSH Prohlížeč
• steroidhydroxylasy MeSH
• systém (enzymů) cytochromů P-450 MeSH