Publications by authors named "Krzysztof Pociecha"

21 Publications

  • Page 1 of 1

Metabolic benefits of novel histamine H receptor ligands in the model of excessive eating: The importance of intrinsic activity and pharmacokinetic properties.

Biomed Pharmacother 2021 Jul 26;142:111952. Epub 2021 Jul 26.

Department of Pharmacological Screening, Jagiellonian University, Medical College, Medyczna 9, PL 30-688 Cracow, Poland. Electronic address:

Aims: One of the therapeutic approaches in the treatment of obesity is the use of histamine H receptor ligands. Histamine plays a significant role in eating behavior because it causes a loss of appetite and is considered to be a satiety signal released during food intake.

Material And Methods: Histamine ligands were selected based on the preliminary studies which included determination of intrinsic activity and selected pharmacokinetic parameters. Female Wistar rats were fed palatable feed for 28 days and simultaneously the tested compounds were administered intraperitoneally at a dose of 10 mg/kg b.w./day. Rats' weight was evaluated daily and calories intake was evaluated once per week. At the end of experiment insulin and glucose tolerance tests was performed. Plasma levels of cholesterol, triglycerides, leptin, insulin, glucose, C-peptide and CRP were also determined. In order to rule out false-positive results the influence of tested compounds on spontaneous activity of rats was monitored.

Results: Animals fed palatable feed and treated with KSK-61 or KSK-63 compounds showed the slowest weight gain which was comparable to the one observed in control animals. Both compounds with the highest pharmacological activity have also similar pharmacokinetic properties with quite long half-life and high volume of distribution indicating that they can freely cross most biological barriers. Some compounds, especially KSK-63, compensated for metabolic disorders.

Conclusion: The presented study proves that search among the active histamine H receptor ligands for the new therapeutic agents to treat obesity is justified. Compounds KSK-61 and KSK-63 can be considered as the leading structures.
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http://dx.doi.org/10.1016/j.biopha.2021.111952DOI Listing
July 2021

A new class of 5-HT receptor antagonists with procognitive and antidepressant properties.

Future Med Chem 2021 Sep 13;13(18):1497-1514. Epub 2021 Jul 13.

Jagiellonian University Medical College, Faculty of Pharmacy, Department of Medicinal Chemistry, 9 Medyczna Street, 30-688, Kraków, Poland.

5-HT receptor antagonists constitute a potential group of drugs in the treatment of CNS diseases. The aim of this study was to search for new procognitive and antidepressant drugs among amide derivatives of aminoalkanoic acids with 5-HT receptor antagonistic properties. Thirty-three amides were designed and evaluated for their drug-likeness. The synthesized compounds were tested for their 5-HT receptor affinity and functional profile. Moreover, their selectivity over 5-HT, 5-HT and D receptors and ability to inhibit phosphodiesterases were evaluated.  A selected 5-HT receptor antagonist ( = 35 nM,  = 4.9 nM) showed procognitive and antidepressant activity . Novel 5-HT receptor antagonists were discovered and shown as potential psychotropic drugs.
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http://dx.doi.org/10.4155/fmc-2020-0363DOI Listing
September 2021

Design and Synthesis of Novel Aminoalkanamides Targeting Neurodegeneration and Symptoms of Alzheimer's Disease.

Curr Med Chem 2021 Feb 14. Epub 2021 Feb 14.

Jagiellonian University Medical College, Faculty of Pharmacy, Department of Medicinal Chemistry, 9 Medyczna Street, 30-688 Kraków. Poland.

Background: There is currently no drug that slows the process of neurodegeneration or alleviates the cognitive and depressive symptoms in patients with Alzheimer's disease. Due to the increasing number of Alzheimer's patients, there is an urgent need to develop novel drugs with neuroprotective, procognitive, and antidepressant properties.

Objective: The aim of this study was to design, synthesize, and evaluate novel aminoalkanamides with serotonin 5-HT1A/5-HT7 receptor affinity and phosphodiesterase (PDE) inhibitory activity as a new approach to combat neurodegeneration and symptoms of Alzheimer's disease.

Methods: The newly designed compounds were synthesized using classical methods of organic chemistry and tested in vitro for their receptor affinity, functional profile, enzyme inhibition, and ADME properties. The neuroprotective effect against H2O2-induced increase of reactive oxygen species level was tested in SH-SY5Y cells. The novel object recognition and forced swimming tests were used to evaluate the procognitive and antidepressant activity, respectively.

Results: Synthesized aminoalkanamides were characterized as potent 5-HT1A receptor antagonists with additional 5-HT7 receptor antagonistic properties and PDE4B inhibitory activity. Selected compound 15 showed neuroprotective, procognitive, and antidepressant properties. In addition, compound 15 revealed suitable ADME properties expressed as a good membrane permeability and a high metabolic stability.

Conclusion: This study revealed a new class of compounds that may be useful in the search for an effective drug in the alleviation of neurodegeneration and symptoms of Alzheimer's disease.
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http://dx.doi.org/10.2174/0929867328666210215113346DOI Listing
February 2021

New imidazopyridines with phosphodiesterase 4 and 7 inhibitory activity and their efficacy in animal models of inflammatory and autoimmune diseases.

Eur J Med Chem 2021 Jan 19;209:112854. Epub 2020 Sep 19.

Jagiellonian University Medical College, Faculty of Pharmacy, Department of Medicinal Chemistry, 9 Medyczna Street, 30-688, Kraków, Poland. Electronic address:

Herein, we describe the rapid synthesis of a focused library of trisubstituted imidazo[4,5-b]pyridines and imidazo[4,5-c]pyridines from 2,4-dichloro-3-nitropyridine using the combination of solution-phase/solid-phase chemistry as new potential anti-inflammatory agents in the treatment of autoimmune diseases. Structure-activity relationship studies, followed by the structure optimization, provided hit compounds (17 and 28) which inhibited phosphodiesterase 4 (PDE4) with IC values comparable to rolipram and displayed different inhibitory potency against phosphodiesterase 7 (PDE7). Among them, compound 17 showed a beneficial effect in all the studied animal models of inflammatory and autoimmune diseases (concanavalin A-induced hepatitis, lipopolysaccharide-induced endotoxemia, collagen-induced arthritis, and MOG-induced encephalomyelitis). In addition, compound 17 showed a favorable pharmacokinetic profile after intraperitoneal administration; it was characterized by a fast absorption from the peritoneal cavity and a relatively long terminal half-life in rats. It was found to penetrate brain barrier in mice. The performed experiments sheds light on the impact of PDE7A inhibition for the efficacy of PDE4 inhibitors in these disease conditions.
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http://dx.doi.org/10.1016/j.ejmech.2020.112854DOI Listing
January 2021

KM-416, a novel phenoxyalkylaminoalkanol derivative with anticonvulsant properties exerts analgesic, local anesthetic, and antidepressant-like activities. Pharmacodynamic, pharmacokinetic, and forced degradation studies.

Eur J Pharmacol 2020 Nov 5;886:173540. Epub 2020 Sep 5.

Department of Bioorganic Chemistry, Jagiellonian University Medical College, Faculty of Pharmacy, 9 Medyczna Street, 30-688, Kraków, Poland.

Anticonvulsant drugs are used to treat a wide range of non-epileptic conditions, including chronic, neuropathic pain. We obtained a phenoxyalkylaminoalkanol derivative, KM-416 which had previously demonstrated a significant anticonvulsant activity and had also been shown to bind to 5-HT, α-receptors and SERT and not to exhibit mutagenic properties. As KM-416 is a promising compound in our search for drug candidates, in the present study we further assessed its pharmacological profile (analgesic, local anesthetic, and antidepressant-like activities) accompanied with patch-clamp studies. Considering the importance of drug safety, its influence on the cardiovascular system was also evaluated. Moreover, KM-416 was subjected to forced degradation and pharmacokinetic studies to examine its stability and pharmacokinetic parameters. KM-416 revealed a significant antinociceptive activity in the tonic - the formalin test, neurogenic - the capsaicin test, and neuropathic pain model - streptozotocin-induced peripheral neuropathy. Moreover, it exerted a local anesthetic effect. In addition, KM-416 exhibited anti-depressant like activity. The results from the patch-clamp studies indicated that KM-416 can inhibit currents elicited by activation of NMDA receptors, while it also exhibited a voltage-dependent inhibition of Na currents. KM-416 did not influence ventricular depolarization and repolarization. Following oral administration, pharmacokinetics of KM-416 was characterized by a rapid absorption in the rat. The brain-to-plasma AUC ratio was 6.7, indicating that KM-416 was well distributed to brain. The forced degradation studies showed that KM-416 was very stable under stress conditions. All these features made KM-416 a promising drug candidate for further development against neuropathic pain and epilepsy.
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http://dx.doi.org/10.1016/j.ejphar.2020.173540DOI Listing
November 2020

Novel anilide and benzylamide derivatives of arylpiperazinylalkanoic acids as 5-HT/5-HT receptor antagonists and phosphodiesterase 4/7 inhibitors with procognitive and antidepressant activity.

Eur J Med Chem 2020 Sep 17;201:112437. Epub 2020 Jun 17.

Jagiellonian University Medical College, Faculty of Pharmacy, Department of Medicinal Chemistry, 9 Medyczna Street, 30-688, Kraków, Poland. Electronic address:

A library of novel anilide and benzylamide derivatives of ω-(4-(2-methoxyphenyl)piperazin-1-yl)alkanoic acids as combined 5-HT/5-HT receptor ligands and phosphodiesterase PDE4B/PDE7A inhibitors was designed using a structure-based drug design approach. The in vitro studies of 33 newly synthesized compounds (7-39) allowed us to identify 22 as the most promising multifunctional 5-HT/5-HT receptor antagonist (5-HTK = 8 nM, K = 0.04 nM; 5-HTK = 451 nM, K = 460 nM) with PDE4B/PDE7A inhibitory activity (PDE4B IC = 80.4 μM; PDE7A IC = 151.3 μM). Compound 22 exerted a very good ability to passively penetrate through biological membranes and a high metabolic stability in vitro. Moreover, the pharmacological evaluation of 22 showed its procognitive and antidepressant properties in rat behavioral tests. Compound 22 at a dose of 3 mg/kg (i.p.) significantly reversed MK-801-induced episodic memory deficits in the novel object recognition test, while at a dose of 10 mg/kg (i.p.) reduced the immobility time of animals (by about 34%) in the forced swimming test. The antidepressant-like effect produced by compound 22 was stronger than that of escitalopram used as a reference drug. This study opens a new perspective in the search for efficacious drugs for the treatment of cognitive and depressive disorders.
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http://dx.doi.org/10.1016/j.ejmech.2020.112437DOI Listing
September 2020

A Novel, Pan-PDE Inhibitor Exerts Anti-Fibrotic Effects in Human Lung Fibroblasts via Inhibition of TGF-β Signaling and Activation of cAMP/PKA Signaling.

Int J Mol Sci 2020 Jun 3;21(11). Epub 2020 Jun 3.

Department of Molecular Pharmacology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.

Phosphodiesterase (PDE) inhibitors are currently a widespread and extensively studied group of anti-inflammatory and anti-fibrotic compounds which may find use in the treatment of numerous lung diseases, including asthma and chronic obstructive pulmonary disease. Several PDE inhibitors are currently in clinical development, and some of them, e.g., roflumilast, are already recommended for clinical use. Due to numerous reports indicating that elevated intracellular cAMP levels may contribute to the alleviation of inflammation and airway fibrosis, new and effective PDE inhibitors are constantly being sought. Recently, a group of 7,8-disubstituted purine-2,6-dione derivatives, representing a novel and prominent pan-PDE inhibitors has been synthesized. Some of them were reported to modulate transient receptor potential ankyrin 1 (TRPA1) ion channels as well. In this study, we investigated the effect of selected derivatives (832-a pan-PDE inhibitor, 869-a TRPA1 modulator, and 145-a pan-PDE inhibitor and a weak TRPA1 modulator) on cellular responses related to airway remodeling using MRC-5 human lung fibroblasts. Compound 145 exerted the most considerable effect in limiting fibroblast to myofibroblasts transition (FMT) as well as proliferation, migration, and contraction. The effect of this compound appeared to depend mainly on its strong PDE inhibitory properties, and not on its effects on TRPA1 modulation. The strong anti-remodeling effects of 145 required activation of the cAMP/protein kinase A (PKA)/cAMP response element-binding protein (CREB) pathway leading to inhibition of transforming growth factor type β (TGF-β) and Smad-dependent signaling in MRC-5 cells. These data suggest that the TGF-β pathway is a major target for PDE inhibitors leading to inhibitory effects on cell responses involved in airway remodeling. These potent, pan-PDE inhibitors from the group of 7,8-disubstituted purine-2,6-dione derivatives, thus represent promising anti-remodeling drug candidates for further research.
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http://dx.doi.org/10.3390/ijms21114008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312375PMC
June 2020

Correction to: Comparative Assessment of the New PDE7 Inhibitor - GRMS-55 and Lisofylline in Animal Models of Immune-Related Disorders: A PK/PD Modeling Approach.

Pharm Res 2020 01 21;37(3):37. Epub 2020 Jan 21.

Department of Pharmacokinetics and Physical Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688, Kraków, Poland.

There was a mistake in the unit of clearance (Cl) in Table II. In addition, the descriptions of V and V were imprecise and the reference number in the footnote below this table should be (9). The corrected Table appears below.
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http://dx.doi.org/10.1007/s11095-020-2764-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050551PMC
January 2020

Comparative Assessment of the New PDE7 Inhibitor - GRMS-55 and Lisofylline in Animal Models of Immune-Related Disorders: A PK/PD Modeling Approach.

Pharm Res 2020 Jan 2;37(2):19. Epub 2020 Jan 2.

Department of Pharmacokinetics and Physical Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688, Kraków, Poland.

Purpose: This study aimed to assess the activity of two phosphodiesterase (PDE) inhibitors, namely GRMS-55 and racemic lisofylline ((±)-LSF)) in vitro and in animal models of immune-mediated disorders.

Methods: Inhibition of human recombinant (hr)PDEs and TNF-alpha release from LPS-stimulated whole rat blood by the studied compounds were assessed in vitro. LPS-induced endotoxemia, concanavalin A (ConA)-induced hepatitis, and collagen-induced arthritis (CIA) animal models were used for in vivo evaluation. The potency of the investigated compounds was evaluated using PK/PD and PK/PD/disease progression modeling.

Results: GRMS-55 is a potent hrPDE7A and hrPDE1B inhibitor, while (±)-LSF most strongly inhibits hrPDE3A and hrPDE4B. GRMS-55 decreased TNF-alpha levels in vivo and CIA progression with IC of 1.06 and 0.26 mg/L, while (±)-LSF with IC of 5.80 and 1.06 mg/L, respectively. Moreover, GRMS-55 significantly ameliorated symptoms of ConA-induced hepatitis.

Conclusions: PDE4B but not PDE4D inhibition appears to be mainly engaged in anti-inflammatory activity of the studied compounds. GRMS-55 and (±)-LSF seem to be promising candidates for future studies on the treatment of immune-related diseases. The developed PK/PD models may be used to assess the anti-inflammatory and anti-arthritic potency of new compounds for the treatment of rheumatoid arthritis and other inflammatory disorders.
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http://dx.doi.org/10.1007/s11095-019-2727-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940354PMC
January 2020

Novel phosphodiesterases inhibitors from the group of purine-2,6-dione derivatives as potent modulators of airway smooth muscle cell remodelling.

Eur J Pharmacol 2019 Dec 6;865:172779. Epub 2019 Nov 6.

Department of Molecular Pharmacology, University of Groningen, Antonius Deusinglaan 1, 9713, AV, Groningen, the Netherlands.

Airway remodelling (AR) is an important pathological feature of chronic asthma and chronic obstructive pulmonary disease. The etiology of AR is complex and involves both lung structural and immune cells. One of the main contributors to airway remodelling is the airway smooth muscle (ASM), which is thickened by asthma, becomes more contractile and produces more extracellular matrix. As a second messenger, adenosine 3',5'-cyclic monophosphate (cAMP) has been shown to contribute to ASM cell (ASMC) relaxation as well as to anti-remodelling effects in ASMC. Phosphodiesterase (PDE) inhibitors have drawn attention as an interesting new group of potential anti-inflammatory and anti-remodelling drugs. Recently, new hydrazide and amide purine-2,6-dione derivatives with anti-inflammatory properties have been synthesized by our team (compounds 1 and 2). We expanded our study of their PDE selectivity profile, ability to increase intracellular cAMP levels, metabolic stability and, above all, their capacity to modulate cell responses associated with ASMC remodelling. The results show that both compounds have subtype specificity for several PDE isoforms (including inhibition of PDE1, PDE3, PDE4 and PDE7). Interestingly, such combined PDE subtype inhibition exerts improved anti-remodelling efficacies against several ASMC-induced responses such as proliferation, contractility, extracellular matrix (ECM) protein expression and migration when compared to other non-selective and selective PDE inhibitors. Our findings open novel perspectives in the search for new chemical entities with dual anti-inflammatory and anti-remodelling profiles in the group of purine-2,6-dione derivatives as broad-spectrum PDE inhibitors.
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http://dx.doi.org/10.1016/j.ejphar.2019.172779DOI Listing
December 2019

Beneficial effects of non-quinazoline α-adrenolytics on hypertension and altered metabolism in fructose-fed rats. A comparison with prazosin.

Nutr Metab Cardiovasc Dis 2019 07 13;29(7):751-760. Epub 2019 Apr 13.

Department of Pharmacodynamics, Faculty of Pharmacy, Medical College, Jagiellonian University, Medyczna 9, 30-688, Kraków, Poland.

Background And Aims: Metabolic syndrome associated with insulin resistance and hypertension is often caused by excessive fructose consumption. Treatment of hypertension in patients with metabolic syndrome is a difficult task as many antihypertensive drugs have adverse effects on the metabolic profile. We investigated if MH-76 and MH-79, non-quinazoline α-adrenoceptor antagonists with an additional ability to stimulate NO/cGMP/K pathway, ameliorates metabolic syndrome in fructose-fed rats. As reference compound prazosin was used.

Methods And Results: Male rats were divided into 5 groups (n = 8) and studied for 18 weeks: group control: standard diet and drinking water; group Fructose: high-fructose diet (20% fructose in drinking water); groups Fructose + MH-76, Fructose + MH-79, Fructose + prazosin: high-fructose diet with subsequent MH-76, MH-79 (5 mg/kg/day ip) or prazosin (0.2 mg/kg/day ip) treatment 12 weeks later. In addition to their antihypertensive effect, the studied compounds reversed endothelial dysfunction, decreased hyperglycemia and hypertriglyceridemia, as well as prevented abdominal adiposity. Moreover, MH-76 reduced insulin resistance and decreased TNF-α concentration and lipid peroxidation in adipose tissue. Prazosin treatment exerted an antihypertensive effect, reduced hyperglycemia but did not improve endothelial dysfunction, insulin resistance, and abdominal adiposity. The lower efficacy of prazosin may be the result of its short half-time and the lack of described pleiotropic effects.

Conclusions: α-adrenoceptor blockade, endothelial protection, TNF-α suppressing and antioxidant activity together with favorable pharmacokinetic parameters determines high efficacy of MH-76, leading to the effective improvement of hemodynamic and metabolic disturbances in metabolic syndrome. The use of non-quinazoline, multiple-targeted α-blockers may be an interesting option for treatment of hypertension with metabolic complications.
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http://dx.doi.org/10.1016/j.numecd.2019.04.003DOI Listing
July 2019

Novel Aryloxyethyl Derivatives of 1-(1-Benzoylpiperidin-4-yl)methanamine as the Extracellular Regulated Kinases 1/2 (ERK1/2) Phosphorylation-Preferring Serotonin 5-HT Receptor-Biased Agonists with Robust Antidepressant-like Activity.

J Med Chem 2019 03 2;62(5):2750-2771. Epub 2019 Mar 2.

Faculty of Pharmacy , Jagiellonian University Medical College , 9 Medyczna Street , 30-688 Kraków , Poland.

Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives were designed as "biased agonists" of serotonin 5-HT receptors. The compounds were tested in signal transduction assays (ERK1/2 phosphorylation, cAMP inhibition, Ca mobilization, and β-arrestin recruitment) which identified ERK1/2 phosphorylation-preferring aryloxyethyl derivatives. The novel series showed high 5-HT receptor affinity, >1000-fold selectivity versus noradrenergic α, dopamine D, serotonin 5-HT, histamine H, and muscarinic M receptors, and favorable druglike properties (CNS-MPO, Fsp, LELP). The lead structure, (3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(pyridin-2-yloxy)ethyl)amino)methyl)piperidin-1-yl)methanone (17, NLX-204), displayed high selectivity in the SafetyScreen44 panel (including hERG channel), high solubility, metabolic stability, and Caco-2 penetration and did not block CYP3A4, CYP2D6 isoenzymes, or P-glycoprotein. Preliminary in vivo studies confirmed its promising pharmacokinetic profile. 17 also robustly stimulated ERK1/2 phosphorylation in rat cortex and showed highly potent (MED = 0.16 mg/kg) and efficacious antidepressant-like activity, totally eliminating immobility in the rat Porsolt test. These data suggest that the present 5-HT receptor-biased agonists could constitute promising antidepressant drug candidates.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00062DOI Listing
March 2019

Influence of inflammatory disorders on pharmacokinetics of lisofylline in rats: implications for studies in humans.

Xenobiotica 2019 Oct 11;49(10):1209-1220. Epub 2018 Dec 11.

b Faculty of Chemistry , Jagiellonian University , Cracow , Poland.

1. Despite the number of favourable properties of lisofylline (LSF), clinical trials on this compound have not yielded the expected results yet. 2. The aims of this study were to evaluate the pharmacokinetics of LSF enantiomers in rats following intravenous, oral and subcutaneous administration of (±)-LSF and to assess the influence of experimental inflammatory disorders, such as multiple organ dysfunction syndrome and severe sepsis on LSF pharmacokinetics. 3. In addition, based on the results obtained an attempt was made to elucidate the possible reasons for the failure of LSF therapy in clinical trials carried out in patients with severe inflammatory disorders. 4. A subcutaneous route of (±)-LSF administration to rats is more favourable than an oral one due to a high bioavailability and a fast absorption of both LSF enantiomers. Pharmacokinetics of LSF in rats is significantly influenced by inflammatory diseases. Too low LSF serum levels might have been one of the reasons for clinical trial failures. A long-term i.v. infusion of LSF seems to be more effective compared to short-term multiple infusions that were used in clinical trials, as it may provide concentrations above IC for inhibition of both TNF-alpha release and cAMP degradation in serum for a longer period of time.
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http://dx.doi.org/10.1080/00498254.2018.1542516DOI Listing
October 2019

Novel amide derivatives of 1,3-dimethyl-2,6-dioxopurin-7-yl-alkylcarboxylic acids as multifunctional TRPA1 antagonists and PDE4/7 inhibitors: A new approach for the treatment of pain.

Eur J Med Chem 2018 Oct 10;158:517-533. Epub 2018 Sep 10.

Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna str, 30-688, Kraków, Poland.

A series of novel amide derivatives of 1,3-dimethyl-2,6-dioxopurin-7-yl-alkylcarboxylic acids designed using a structure-based computational approach was synthesized and assayed to evaluate their ability to block human TRPA1 channel and inhibit PDE4B/7A activity. We identified compounds 16 and 27 which showed higher potency against TRPA1 compared to HC-030031. In turn, compound 36 was the most promising multifunctional TRPA1 antagonist and PDE4B/7A dual inhibitor with IC values in the range of that of the reference rolipram and BRL-50481, respectively. Compound 36 as a combined TRPA1/PDE4B/PDE7A ligand was characterized by a distinct binding mode in comparison to 16 and 27, in the given protein targets. The inhibition of both cAMP-specific PDE isoenzymes resulted in a strong anti-TNF-α effect of 36in vivo. Moreover, the potent anti-inflammatory and analgesic efficacy of 36 was observed in animal models of pain and inflammation (formalin test in mice and carrageenan-induced paw edema in rats). This compound also displayed significant antiallodynic properties in the early phase of chemotherapy-induced peripheral neuropathy in mice. In turn, the pure TRPA1 antagonists 16 and 27 revealed a statistically significant antiallodynic effect in the formalin test and in the von Frey test performed in both phases of oxaliplatin-induced allodynia. Antiallodynic activity of the test compounds 16, 27 and 36 was observed at a dose range comparable to that of the reference drug - pregabalin. In conclusion, the proposed approach of pain treatment based on the concomitant blocking of TRPA1 channel and PDE4B/7A inhibitory activity appears to be interesting research direction for the future search for novel analgesics.
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http://dx.doi.org/10.1016/j.ejmech.2018.09.021DOI Listing
October 2018

The impact of polymers on 3D microstructure and controlled release of sildenafil citrate from hydrophilic matrices.

Eur J Pharm Sci 2018 Jul 19;119:234-243. Epub 2018 Apr 19.

Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, Jagiellonian University Collegium Medicum, Cracow, Poland.

Sildenafil citrate has short biological half-life in humans. Thus, matrix tablets of controlled release were designed and prepared by compaction on the basis of hydrophilic polymers, i.e. HPMC, sodium alginate, carbomer, poloxamer and their mixtures. The impact of these polymers on sildenafil release in vitro and its pharmacokinetics in vivo was evaluated. Since drug release rate from hydrophilic matrices can be govern by the porosity of the matrix, the microstructure of tablets was studied using X-ray microcomputed tomography. 3D network of either open (percolating) or closed (non-percolating) pores was reconstructed. The tortuosity and the diameter of both kinds of pores were determined. Their spatial distribution within the matrix was analyzed in linear and radial direction. Polymer-dependent characteristics of the open pores (Ø > 2 μm) architecture was shown. The release profiles of sildenafil from matrix tablets fitted to Korsmeyer-Peppas model (r: 0.9331-0.9993) with either Fickian diffusion or anomalous transport involved. Mean dissolution time (MDT) from tablets made of HPMC, carbomer or a mixture of HPMC and sodium alginate (2:1) was ca. 100 min, which was more than twelve times longer as compared to matrices prepared of silicified microcrystalline cellulose (MDT = 8 min). MDT correlated with the number of the open pores (Pearson's r = 0.94). Sustained release of sildenafil from ground carbomer tablets reflected in the slow absorption of the drug (t = 5.0 ± 1.2 h) in vivo and the relative bioavailability of 151%. Interestingly, the relative bioavailability of sildenafil from binary matrices composed of HPMC and sodium alginate (2:1) was almost four times higher than that of sildenafil alone.
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http://dx.doi.org/10.1016/j.ejps.2018.04.023DOI Listing
July 2018

Novel butanehydrazide derivatives of purine-2,6-dione as dual PDE4/7 inhibitors with potential anti-inflammatory activity: Design, synthesis and biological evaluation.

Eur J Med Chem 2018 Feb 4;146:381-394. Epub 2018 Feb 4.

Department of Medicinal Chemistry, Jagiellonian University, Medical College, Medyczna 9, 30-688, Kraków, Poland.

A novel butanehydrazide derivatives of purine-2,6-dione designed using a ligand-based approach were synthesized and their in vitro activity against both PDE4B and PDE7A isoenzymes was assessed. The 7,8-disubstituted purine-2,6-dione derivatives 31, 34, 37, and 40 appeared to be the most potent PDE4/7 inhibitors with IC values in the range of that of the reference rolipram and BRL-50481, respectively. Moreover, docking studies explained the importance of N-(2,3,4-trihydroxybenzylidene)butanehydrazide substituent in position 7 of purine-2,6-dione core for dual PDE4/7 inhibitory properties. The inhibition of both the cAMP-specific PDE isoenzymes resulted in a strong anti-TNF-α effect. Compounds 31, 34, and 37 in the in vivo study in rats with LPS-induced endotoxemia decreased the maximum concentration of this proinflammatory cytokine by 53, 84 and 88%, respectively.
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http://dx.doi.org/10.1016/j.ejmech.2018.01.068DOI Listing
February 2018

Pharmacokinetic study of tianeptine and its active metabolite MC5 in rats following different routes of administration using a novel liquid chromatography tandem mass spectrometry analytical method.

Naunyn Schmiedebergs Arch Pharmacol 2018 Feb 12;391(2):185-196. Epub 2017 Dec 12.

Department of Pharmacokinetics and Physical Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland.

Tianeptine is an atypical antidepressant with a unique mechanism of action and recently it has been also reported that its major metabolite, compound MC5, possesses pharmacological activity similar to that of the parent drug. The current study aims to investigate the pharmacokinetics (PK) of both tianeptine and MC5 after intravenous or intraperitoneal administration of the parent drug as well as the metabolic ratio of MC5 in rats. To achieve these goals an LC-MS/MS method using the small sample volume for the quantitation of tianeptine and its active metabolite MC5 in rat plasma and liver perfusate has been developed and validated. Following an intravenous administration of tianeptine pharmacokinetic parameters were calculated by non-compartmental analysis. The average tianeptine volume of distribution at steady state was 2.03 L/kg and the systemic clearance equaled 1.84 L/h/kg. The mean elimination half-lives of tianeptine and MC5 metabolite were 1.16 and 7.53 h, respectively. The hepatic clearance of tianeptine determined in the isolated rat liver perfusion studies was similar to the perfusate flow rate despite the low metabolic ratio of MC5. Mass spectrometric analysis of rat bile indicated that tianeptine and MC5 metabolite are eliminated with bile as glucuronide and glutamine conjugates. Bioavailability of tianeptine after its intraperitoneal administration was 69%. The PK model with a metabolite compartment developed in this study for both tianeptine and MC5 metabolite after two routes of administration may facilitate tianeptine dosage selection for the prospective pharmacological experiments.
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http://dx.doi.org/10.1007/s00210-017-1448-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778159PMC
February 2018

ANTI-INFLAMMATORY AND ANTIOXIDANT ACTIVITY OF 8-METHOXY-1,3-DIMETHYL-2,6-DIOXO-PURIN-7-YL DERIVATIVES WITH TERMINAL CARBOXYLIC, ESTER OR AMIDE MOIETIES IN ANIMAL MODELS.

Acta Pol Pharm 2016 May-Jun;73(3):761-70

The previous studies in a series of 8-methoxy-1,3-dimethyl-2,6-dioxo-purin-7-yl derivatives revealed their analgesic properties. We extended the study with these compounds in aim to assess their impact on inflammatory process. For this purpose we used: the zymosan-induced peritonitis and the carrageenan-induced edema model. Furthermore, the antioxidant activity of the investigated compounds by the FRAP assay was determined. For the most active derivatives from evaluated series their influence on plasma TNF-α level was also tested in vivo. All investigated purine-2,6-dione derivatives 1-11 decreased neutrophils count and inhibited intensity of early vascular permeability. Furthermore, all evaluated compounds reduced the volume of edema caused by subcutaneous injection of carrageenan. Derivatives 1 (with ester moiety), 3 and 4 (with carboxylic group) showed the highest activity in the zymosan-induced peritonitis. In addition, a significant inhibition of plasma TNF-α level in rats with endotoxemia was observed following intraperitoneal administration of these compounds. In turn, compounds 6 and 8-11 containing amide moiety showed the greatest anti-inflammatory (antiedematous) effect in the carrageenan-induced paw edema model. All compounds did not show significant antioxidant properties. The present studies revealed that the presented purine-2,6-dione derivatives exhibit a significant anti-inflammatory activity and this effect may result from their ability to lower TNF-α level.
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September 2016

[Contemporary concepts in studies on cyclic AMP and its role in the inflammatory reaction].

Postepy Hig Med Dosw (Online) 2015 Jul 14;69:777-98. Epub 2015 Jul 14.

Zakład Farmakokinetyki i Farmacji Fizycznej, Wydział Farmaceutyczny, Uniwersytet Jagielloński Collegium Medicum w Krakowie.

Although cyclic AMP (cAMP) was discovered more than 50 years ago, new reports of unknown functions of this nucleotide still appear in the literature. It is synthesized from adenosine triphosphate in a reaction catalysed by adenylyl cyclase. In mammalian cells nine membrane-associated and one soluble adenylyl cyclase isoforms occur. Most of them interact with Gs- or Gi-protein coupled receptors. The only way of cAMP degradation is the reaction of hydrolysis catalyzed by phosphodiesterase. In humans there are 11 families of these enzymes, which differ in substrate affinity, structure, place of occurrence and mechanism of regulation. Modulation of activity of these enzymes is an important direction in the search for new drugs. The effectors of cAMP are: protein kinase A (PKA), Epac proteins, and cAMP-dependent ion channels. In the course of the inflammatory response, the increase in cAMP level may lead to an increase in IL-10 expression, inhibition of TNF-α, IL-12, and MIP-1β release, as well as to a reduction inthe permeability of blood vessels. In addition, cAMP regulates the process of phagocytosis. In the majority of cases, acting via PKA it induces cell apoptosis, and by activating Epac proteins it inhibits cell death. It has been shown that the levels of cAMP vary in different intracellular spaces due to the discretely positioned proteins responsible for its synthesis and breakdown. Moreover, the enzymatic pathway responsible for the extracellular degradation of cAMP has been discovered. Two transporters, ABCC4 and ABCC5, are involved in the transport of cAMP outside the cells. Administration of drugs modulating the level of this nucleotide to rodents leads to changes in its concentrations in blood and/or animal tissues. Progress in research on cAMP has become possible to a large extent due to the emergence of new analytical methods for the determination of its concentrations in biological material.
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http://dx.doi.org/10.5604/17322693.1161412DOI Listing
July 2015

Sensitive and precise HPLC method with back-extraction clean-up step for the determination of sildenafil in rat plasma and its application to a pharmacokinetic study.

Biomed Chromatogr 2015 Oct 9;29(10):1559-66. Epub 2015 Apr 9.

Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, Jagiellonian University, Medical College, Cracow, Poland.

A sensitive HPLC method was developed and validated for the determination of sildenafil concentrations in rat plasma (200 μL) using a liquid-liquid extraction procedure and paroxetine as an internal standard. In order to eliminate interferences and improve the peak shape, a back-extraction into an acidic solution was utilized. Chromatographic separation was achieved on a cyanopropyl bonded-phase column with a mobile phase composed of 50 m m potassium dihydrogen phosphate buffer (pH 4.5) and acetonitrile (75:25, v/v), pumped at the flow rate of 1 mL/min. A UV detector was set at 230 nm. A calibration curve was constructed within a concentration range from 10 to 1500 ng/mL. The limit of detection was 5 ng/mL. The inter- and intra-day precisions of the assay were in the ranges 2.91-7.33 and 2.61-6.18%, respectively, and the accuracies for inter- and intra-day runs were within 0.14-3.92 and 0.44-2.96%, respectively. The recovery of sildenafil was 85.22 ± 4.54%. Tests confirmed the stability of sildenafil in plasma during three freeze-thaw cycles and during long-term storage at -20 and -80°C for up to 2 months. The proposed method was successfully applied to a pharmacokinetic study in rats.
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http://dx.doi.org/10.1002/bmc.3459DOI Listing
October 2015

Physiologically based modeling of lisofylline pharmacokinetics following intravenous administration in mice.

Eur J Drug Metab Pharmacokinet 2016 Aug 8;41(4):403-12. Epub 2015 Feb 8.

Department of Pharmacokinetics and Physical Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688, Cracow, Poland.

Lisofylline (LSF), is the R-(-) enantiomer of the metabolite M1 of pentoxifylline, and is currently under development for the treatment of type 1 diabetes. The aim of the study was to develop a physiologically based pharmacokinetic (PBPK) model of LSF in mice and to perform simulations in order to predict LSF concentrations in human serum and tissues following intravenous and oral administration. The concentrations of LSF in serum, brain, liver, kidneys, lungs, muscle, and gut were determined at different time points over 60 min by a chiral HPLC method with UV detection following a single intravenous dose of LSF to male CD-1 mice. A PBPK model was developed to describe serum pharmacokinetics and tissue distribution of LSF using ADAPT II software. All pharmacokinetic profiles were fitted simultaneously to obtain model parameters. The developed model characterized well LSF disposition in mice. The estimated intrinsic hepatic clearance was 5.427 ml/min and hepatic clearance calculated using the well-stirred model was 1.22 ml/min. The renal clearance of LSF was equal to zero. On scaling the model to humans, a good agreement was found between the predicted by the model and presented in literature serum LSF concentration-time profiles following an intravenous dose of 3 mg/kg. The predicted LSF concentrations in human tissues following oral administration were considerably lower despite the twofold higher dose used and may not be sufficient to exert a pharmacological effect. In conclusion, the mouse is a good model to study LSF pharmacokinetics following intravenous administration. The developed PBPK model may be useful to design future preclinical and clinical studies of this compound.
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http://dx.doi.org/10.1007/s13318-015-0260-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4954844PMC
August 2016
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