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European Journal of Heart Failure Jan 2017
Topics: Heart Failure; Humans; Phosphodiesterase 5 Inhibitors; Piperazines; Sildenafil Citrate; Stroke Volume
PubMed: 27873389
DOI: 10.1002/ejhf.690 -
Osteoarthritis and Cartilage Feb 2022A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) is a key enzyme in degradation of cartilage in osteoarthritis (OA). We report the...
OBJECTIVE
A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) is a key enzyme in degradation of cartilage in osteoarthritis (OA). We report the pharmacological characterization of GLPG1972/S201086, a new, potent and selective small-molecule ADAMTS5 inhibitor.
METHODS
Potency and selectivity of GLPG1972/S201086 for ADAMTS5 were determined using fluorescently labeled peptide substrates. Inhibitory effects of GLPG1972/S201086 on interleukin-1α-stimulated glycosaminoglycan release in mouse femoral head cartilage explants and on interleukin-1β-stimulated release of an ADAMTS5-derived aggrecan neoepitope (quantified with ELISA) in human articular cartilage explants were determined. In the destabilization of the medial meniscus (DMM) mouse and menisectomized (MNX) rat models, effects of oral GLPG1972/S201086 on relevant OA histological and histomorphometric parameters were evaluated.
RESULTS
GLPG1972/S201086 inhibited human and rat ADAMTS5 (IC ± SD: 19 ± 2 nM and <23 ± 1 nM, respectively), with 8-fold selectivity over ADAMTS4, and 60->5,000-fold selectivity over other related proteases in humans. GLPG1972/S201086 dose-dependently inhibited cytokine-stimulated aggrenolysis in mouse and human cartilage explants (100% at 20 μM and 10 μM, respectively). In DMM mice, GLPG1972/S201086 (30-120 mg/kg b.i.d) vs vehicle reduced femorotibial cartilage proteoglycan loss (23-37%), cartilage structural damage (23-39%) and subchondral bone sclerosis (21-36%). In MNX rats, GLPG1972/S201086 (10-50 mg/kg b.i.d) vs vehicle reduced cartilage damage (OARSI score reduction, 6-23%), and decreased proteoglycan loss (∼27%) and subchondral bone sclerosis (77-110%).
CONCLUSIONS
GLPG1972/S201086 is a potent, selective and orally available ADAMTS5 inhibitor, demonstrating significant protective efficacy on both cartilage and subchondral bone in two relevant in vivo preclinical OA models.
Topics: Animals; Humans; Mice; Rats; ADAMTS5 Protein; Piperazines
PubMed: 34626798
DOI: 10.1016/j.joca.2021.08.012 -
European Journal of Drug Metabolism and... Jan 2021Cariprazine, a dopamine D-preferring D/D receptor partial agonist, is approved for the treatment of adults with schizophrenia (1.5-6 mg/day) and manic/mixed...
BACKGROUND AND OBJECTIVES
Cariprazine, a dopamine D-preferring D/D receptor partial agonist, is approved for the treatment of adults with schizophrenia (1.5-6 mg/day) and manic/mixed (3-6 mg/day) episodes associated with bipolar I disorder. This population pharmacokinetic analysis describes the concentration-time profiles of cariprazine and its two major active metabolites, desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR). Additionally, the potential impact of patient characteristics, creatinine clearance, and cytochrome P450 2D6 (CYP2D6) metabolizer status on the pharmacokinetics of cariprazine and its metabolites was evaluated.
METHODS
Data from three phase 1 and ten phase 2/3 studies in adult patients with schizophrenia or bipolar mania were included. Nonlinear mixed-effects pharmacokinetic modeling was performed using the NONMEM software package. Compartmental modeling was performed sequentially with the cariprazine elimination rate used as the DCAR formation rate and likewise the elimination rate of DCAR used with a delay as the DDCAR formation rate.
RESULTS
Cariprazine pharmacokinetics were described by a three-compartment model with zero-order input of the dose to a depot compartment followed by first-order absorption and first-order elimination. DCAR and DDCAR pharmacokinetics were described by two-compartment models with linear elimination. Statistically significant predictors of pharmacokinetic parameters included weight, sex, and race, though differences in exposures were not large enough to require an adjustment in dose. Creatinine clearance was not a statistically significant predictor of drug clearance, and a post hoc analysis found that CYP2D6 metabolizer status was not associated with changes in exposure levels for cariprazine, DCAR, or DDCAR. The median time to 90% of steady state was approximately 1 week for cariprazine and DCAR and 3 weeks for DDCAR.
CONCLUSIONS
Population pharmacokinetic modeling provided a quantitative description of the concentration-time profile of cariprazine and its metabolites.
Topics: Adolescent; Adult; Antipsychotic Agents; Clinical Trials as Topic; Databases, Factual; Female; Humans; Male; Middle Aged; Models, Biological; Piperazines; Schizophrenia; Young Adult
PubMed: 33141308
DOI: 10.1007/s13318-020-00650-4 -
PloS One 2018A new class of TSCs containing piperazine (piperazinylogs) of Triapine, was designed to fulfill the di-substitution pattern at the TSCs N4 position, which is a crucial...
A new class of TSCs containing piperazine (piperazinylogs) of Triapine, was designed to fulfill the di-substitution pattern at the TSCs N4 position, which is a crucial prerequisite for the high activity of the previously obtained TSC compounds-DpC and Dp44mT. We tested the important physicochemical characteristics of the novel compounds L1-L12. The studied ligands are neutral at physiological pH, which allows them to permeate cell membranes and bind cellular Fe pools more readily than less lipid-soluble ligands, e.g. DFO. The selectivity and anti-cancer activity of the novel TSCs were examined in a variety of cancer cell types. In general, the novel compounds demonstrated the greatest promise as anti-cancer agents with both a potent and selective anti-proliferative activity. We investigated the mechanism of action more deeply, and revealed that studied compounds inhibit the cell cycle (G1/S phase). Additionally we detected apoptosis, which is dependent on cell line's specific genetic profile. Accordingly, structure-activity relationship studies suggest that the combination of the piperazine ring with Triapine allows potent and selective anticancer chelators that warrant further in vivo examination to be identified. Significantly, this study proved the importance of the di-substitution pattern of the amine N4 function.
Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Copper; G1 Phase; Humans; Iron; Piperazine; Piperazines; Pyridines; S Phase; Structure-Activity Relationship; Thiosemicarbazones
PubMed: 29652894
DOI: 10.1371/journal.pone.0188767 -
European Journal of Pharmaceutical... Nov 2020Toll-like receptor 4 (TLR4) recognizes various endogenous and microbial ligands and is an essential part in the innate immune system. TLR4 signaling initiates...
Mitoxantrone, pixantrone and mitoxantrone (2-hydroxyethyl)piperazine are toll-like receptor 4 antagonists, inhibit NF-κB activation, and decrease TNF-alpha secretion in primary microglia.
Toll-like receptor 4 (TLR4) recognizes various endogenous and microbial ligands and is an essential part in the innate immune system. TLR4 signaling initiates transcription factor NF-κB and production of proinflammatory cytokines. TLR4 contributes to the development or progression of various diseases including stroke, neuropathic pain, multiple sclerosis, rheumatoid arthritis and cancer, and better therapeutics are currently sought for these conditions. In this study, a library of 140 000 compounds was virtually screened and a resulting hit-list of 1000 compounds was tested using a cellular reporter system. The topoisomerase II inhibitor mitoxantrone and its analogues pixantrone and mitoxantrone (2-hydroxyethyl)piperazine were identified as inhibitors of TLR4 and NF-κB activation. Mitoxantrone was shown to bind directly to the TLR4, and pixantrone and mitoxantrone (2-hydroxyethyl)piperazine were shown to inhibit the production of proinflammatory cytokines such as tumor necrosis factor alpha (TNFα) in primary microglia. The inhibitory effect on NF-κB activation or on TNFα production was not mediated through cytotoxity at ≤ 1 µM concentration for pixantrone and mitoxantrone (2-hydroxyethyl)piperazine treated cells, as assessed by ATP counts. This study thus identifies a new mechanism of action for mitoxantrone, pixantrone, and mitoxantrone (2-hydroxyethyl)piperazine through the TLR4.
Topics: Isoquinolines; Microglia; Mitoxantrone; NF-kappa B; Piperazine; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha
PubMed: 32730846
DOI: 10.1016/j.ejps.2020.105493 -
BMC Genomics Nov 2020Auxins play key roles in the phytohormone network. Early auxin response genes in the AUX/IAA, SAUR, and GH3 families show functional redundancy, which makes it very...
BACKGROUND
Auxins play key roles in the phytohormone network. Early auxin response genes in the AUX/IAA, SAUR, and GH3 families show functional redundancy, which makes it very difficult to study the functions of individual genes based on gene knockout analysis or transgenic technology. As an alternative, chemical genetics provides a powerful approach that can be used to address questions relating to plant hormones.
RESULTS
By screening a small-molecule chemical library of compounds that can induce abnormal seedling and vein development, we identified and characterized a piperazine compound 1-[(4-bromophenoxy) acetyl]-4-[(4-fluorophenyl) sulfonyl] piperazine (ASP). The Arabidopsis DR5::GFP line was used to assess if the effects mentioned were correlated with the auxin response, and we accordingly verified that ASP altered the auxin-related pathway. Subsequently, we examined the regulatory roles of ASP in hypocotyl and root development, auxin distribution, and changes in gene expression. Following ASP treatment, we detected hypocotyl elongation concomitant with enhanced cell elongation. Furthermore, seedlings showed retarded primary root growth, reduced gravitropism and increased root hair development. These phenotypes were associated with an increased induction of DR5::GUS expression in the root/stem transition zone and root tips. Auxin-related mutants including tir1-1, aux1-7 and axr2-1 showed phenotypes with different root-development pattern from that of the wild type (Col-0), and were insensitive to ASP. Confocal images of propidium iodide (PI)-stained root tip cells showed no detectable damage by ASP. Furthermore, RT-qPCR analyses of two other genes, namely, Ethylene Response Factor (ERF115) and Mediator 18 (MED18), which are related to cell regeneration and damage, indicated that the ASP inhibitory effect on root growth was not attributable to toxicity. RT-qPCR analysis provided further evidence that ASP induced the expression of early auxin-response-related genes.
CONCLUSIONS
ASP altered the auxin response pathway and regulated Arabidopsis growth and development. These results provide a basis for dissecting specific molecular components involved in auxin-regulated developmental processes and offer new opportunities to discover novel molecular players involved in the auxin response.
Topics: Arabidopsis; Arabidopsis Proteins; Gene Expression Regulation, Plant; Indoleacetic Acids; Mediator Complex; Mutation; Piperazine; Plant Roots
PubMed: 33176686
DOI: 10.1186/s12864-020-07203-8 -
PloS One 2017The Antibiogram properties of 1-chloro-2-isocyanatoethane derivatives of thiomorpholine (CTC), piperazine (CPC) and morpholine (CMC) were evaluated by the approved agar...
The Antibiogram properties of 1-chloro-2-isocyanatoethane derivatives of thiomorpholine (CTC), piperazine (CPC) and morpholine (CMC) were evaluated by the approved agar well diffusion, the minimum inhibitory concentration (MIC) and in silico techniques. A total of fourteen microbial cultures consisting of ten bacteria and four yeast strains were used in the biological study while affinity of the compounds for DNA gyrase, a validated antibacterial drug target, was investigated by docking method. Results indicate that both thiomorpholine and piperazine had zero activity against the Gram negative organisms tested. With morpholine, similar result was obtained except that cultures of Escherichia coli (ATCC 15442) and Salmonella typhi (ATCC 6539) presented with weak sensitivity (7-8 mm) as shown by the inhibition zone diameter (IZD) measurement. The Gram positive organisms were more sensitive to morpholine than the other compounds. The highest IZD values of 15-18 mm were achieved except for Streptococcus pneumoniae (ATCC 49619) in which mobility of the compound stopped after 12 mm. S. pneumoniae was resistant to both thiomorpholine and piperazine. The yeast strains were not sensitive to any of the studied compounds investigated. The MIC tests evaluated against a reference antibiotic show that while morpholine was most active at 4 μg.ml-1 against both B. cereus ATCC (14579) and B. subtilis, the least active compound was thiomorpholine which inhibited S. aureus (ATCC 25923) at 64 μg.ml-1. The three compounds demonstrated high affinity for the target protein (DNA gyrase) ranging from -4.63 to -5.64 Kcal/mol and even showed better ligand efficiencies than three known antibiotics; chlorobiocin, ciprofloxacin and tetracycline. This study identified the studied compounds as potential antibiotic leads with acceptable physicochemical properties and gave the molecular basis for the observed interactions between the compounds and the target protein which can be harnessed in structural optimization process.
Topics: Anti-Bacterial Agents; Biological Availability; Computer Simulation; Gram-Negative Bacteria; Isocyanates; Microbial Sensitivity Tests; Molecular Docking Simulation; Morpholines; Piperazines
PubMed: 28107379
DOI: 10.1371/journal.pone.0170150 -
International Journal of Molecular... Feb 2023A series of 15 new derivatives of 6-acetyl-7-hydroxy-4-methylcoumarin containing a piperazine group were designed with the help of computational methods and were...
A series of 15 new derivatives of 6-acetyl-7-hydroxy-4-methylcoumarin containing a piperazine group were designed with the help of computational methods and were synthesized to study their affinity for the serotonin 5-HT and 5-HT receptors. Among them, 6-acetyl-7-{4-[4-(3-bromophenyl)piperazin-1-yl]butoxy}-4-methylchromen-2-one () and 6-acetyl-7-{4-[4-(2-chlorophenyl)piperazin-1-yl]butoxy}-4-methylchromen-2-one () exhibited excellent activity for 5-HT receptors with Ki values 0.78 (0.4-1.4) nM and 0.57 (0.2-1.3) nM, respectively, comparable to the Ki values of 8-OH-DPAT (0.25 (0.097-0.66) nM). The equilibrium dissociation constant values of the tested compounds showed differential intrinsic activities of the agonist and antagonist modes.
Topics: Serotonin; Receptor, Serotonin, 5-HT1A; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Heterocyclic Compounds; Piperazines; Receptor, Serotonin, 5-HT2A
PubMed: 36769117
DOI: 10.3390/ijms24032779 -
Journal of Enzyme Inhibition and... Dec 2021Molecular hybridisation of four bioactive fragments piperazine, substituted-benzofuran, amino acids, and 2,4-dinitrobenzenesulfonamide as single molecular architecture...
Molecular hybridisation of four bioactive fragments piperazine, substituted-benzofuran, amino acids, and 2,4-dinitrobenzenesulfonamide as single molecular architecture was designed. A series of new hybrids were synthesised and subjected to evaluation for their inhibitory activity against () H37Rv. - and found to exhibit MIC as 1.56 µg/mL, equally active as ethambutol whereas displayed MIC 0.78 µg/mL were superior to ethambutol. Tested compounds demonstrated an excellent safety profile with very low toxicity, good selectivity index, and antioxidant properties. All the newly synthesised compounds were thoroughly characterised by analytical methods. The result was further supported by molecular modelling studies on the crystal structure of enoyl reductase.
Topics: Amides; Antitubercular Agents; Benzenesulfonates; Benzofurans; Cell Line, Tumor; Drug Design; Drug Screening Assays, Antitumor; Humans; Microbial Sensitivity Tests; Molecular Docking Simulation; Mycobacterium tuberculosis; Piperazine; Spectrum Analysis
PubMed: 34325595
DOI: 10.1080/14756366.2021.1956914 -
Protein & Cell Mar 2023
Topics: Ferroptosis; Piperazines; Cell Line, Tumor
PubMed: 36929006
DOI: 10.1093/procel/pwac007