-
Molecules (Basel, Switzerland) Dec 2022We developed a straightforward synthetic route to pharmacologically important 1,5-substituted pyrrolidin-2-ones from donor-acceptor cyclopropanes bearing an ester group...
We developed a straightforward synthetic route to pharmacologically important 1,5-substituted pyrrolidin-2-ones from donor-acceptor cyclopropanes bearing an ester group as one of the acceptor substituents. This method includes a Lewis acid-catalyzed opening of the donor-acceptor cyclopropane with primary amines (anilines, benzylamines, etc.) to γ-amino esters, followed by in situ lactamization and dealkoxycarbonylation. The reaction has a broad scope of applicability; a variety of substituted anilines, benzylamines, and other primary amines as well as a wide range of donor-acceptor cyclopropanes bearing (hetero)aromatic or alkenyl donor groups and various acceptor substituents can be involved in this transformation. In this process, donor-acceptor cyclopropanes react as 1,4-,-dielectrophiles, and amines react as 1,1-dinucleophiles. The resulting di- and trisubstituted pyrrolidin-2-ones can be also used in subsequent chemistry to obtain various nitrogen-containing polycyclic compounds of interest to medicinal chemistry and pharmacology, such as benz[]indolizidine derivatives.
Topics: Aniline Compounds; Molecular Structure; Benzylamines; Cyclopropanes; Lewis Acids; Amines
PubMed: 36500574
DOI: 10.3390/molecules27238468 -
Molecules (Basel, Switzerland) Nov 202117β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3) is expressed at high levels in testes and seminal vesicles; it is also present in prostate tissue and involved in...
17β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3) is expressed at high levels in testes and seminal vesicles; it is also present in prostate tissue and involved in gonadal and non-gonadal testosterone biosynthesis. The enzyme is membrane-bound, and a crystal structure is not yet available. Selective aryl benzylamine-based inhibitors were designed and synthesised as potential agents for prostate cancer therapeutics through structure-based design, using a previously built homology model with docking studies. Potent, selective, low nanomolar IC 17β-HSD3 inhibitors were discovered using -(2-([2-(4-chlorophenoxy)phenylamino]methyl)phenyl)acetamide (). The most potent compounds have IC values of approximately 75 nM. Compound , -[2-(1-Acetylpiperidin-4-ylamino)benzyl]--[2-(4-chlorophenoxy)phenyl]acetamide, has an IC of 76 nM, while compound , -(2-(1-[2-(4-chlorophenoxy)-phenylamino]ethyl)phenyl)acetamide, has an IC of 74 nM. Racemic -allyl derivative (IC of 520 nM) was easily formed from in good yield and, to determine binding directionality, its enantiomers were separated by chiral chromatography. Absolute configuration was determined using single crystal X-ray crystallography. Only the -(+)-enantiomer () was active with an IC of 370 nM. Binding directionality was predictable through our in silico docking studies, giving confidence to our model. Importantly, all novel inhibitors are selective over the type 2 isozyme of 17β-HSD2 and show <20% inhibition when tested at 10 µM. Lead compounds from this series are worthy of further optimisation and development as inhibitors of testosterone production by 17β-HSD3 and as inhibitors of prostate cancer cell growth.
Topics: 17-Hydroxysteroid Dehydrogenases; Benzylamines; Cell Line, Tumor; Crystallography, X-Ray; Enzyme Inhibitors; Humans; Inhibitory Concentration 50; Male; Molecular Docking Simulation; Prostate; Prostatic Neoplasms; Structure-Activity Relationship; Testosterone
PubMed: 34885749
DOI: 10.3390/molecules26237166 -
Neurologia (Barcelona, Spain) Mar 2012The vitamin K antagonists (VKA) available for stroke prevention in patients with atrial fibrillation have many drawbacks due to their difficult clinical use and high... (Review)
Review
The vitamin K antagonists (VKA) available for stroke prevention in patients with atrial fibrillation have many drawbacks due to their difficult clinical use and high risk of bleeding. Currently, several drugs are being developed as possible substitutes for VKA that have many advantages such as the lack of monitoring requirement and scarce pharmacologic and food interactions. The present article provides an update on the new oral anticoagulants that are in a more advanced stage of clinical research, their pharmacologic properties, advantages and disadvantages and their results in recent clinical trials.
Topics: Administration, Oral; Anticoagulants; Azetidines; Benzimidazoles; Benzylamines; Clinical Trials as Topic; Dabigatran; Drug Monitoring; Drugs, Investigational; Hemorrhage; Humans; Morpholines; Multicenter Studies as Topic; Patient Care Planning; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiophenes; Thrombophilia; Vitamin K; beta-Alanine
PubMed: 22682208
DOI: 10.1016/S0213-4853(12)70006-3 -
Drug Design, Development and Therapy 2022Cross-sensitization of pelvic organs is one theory for why symptoms of gut sickness and interstitial cystitis/bladder pain syndrome overlap. Experimental colitis has...
BACKGROUND
Cross-sensitization of pelvic organs is one theory for why symptoms of gut sickness and interstitial cystitis/bladder pain syndrome overlap. Experimental colitis has been shown to trigger bladder hyperactivity and hyperalgesia in rats. The chemokine receptor CXCR4 plays a key role in bladder function and central sensitization. We aim to study the role of CXCR4 and its inhibitor AMD3100 in colon-bladder cross-organ sensitization.
METHODS
The colitis model was established by rectal infusion of trinitrobenzene sulfonic acid. Western blot and immunofluorescence were used to assess the expression and distribution of CXCR4. Intrathecal injection of AMD3100 (a CXCR4 inhibitor) and PD98059 (an ERK inhibitor) were used to inhibit CXCR4 and downstream extracellular signal-regulated kinase (ERK) in the spinal cord and dorsal root ganglion (DRG). Intravesical perfusion of resiniferatoxin was performed to measure the pain behavior counts of rats, and continuous cystometry was performed to evaluate bladder voiding function.
RESULTS
Compared to the control group, CXCR4 was expressed more in bladder mucosa and colon mucosa, L6-S1 dorsal root ganglion (DRG), and the corresponding segment of the spinal dorsal horn (SDH) in rats with colitis. Moreover, intrathecal injection of the AMD3100 suppressed bladder overactivity, bladder hyperalgesia, and mastocytosis symptoms caused by colitis. Furthermore, AMD3100 effectively inhibited ERK activation in the spinal cord induced by experimental colitis. Finally, treatment with PD98059 alleviated bladder overactivity and hyperalgesia caused by colitis.
CONCLUSION
Increased CXCR4 in the DRG and SDH contributes to colon inflammation-induced bladder overactivity and hyperalgesia partly via the phosphorylation of spinal ERK. Treatment targeting the CXCR4/ERK pathway might provide a potential new approach for the comorbidity between the digestive system and the urinary system.
Topics: Animals; Benzylamines; Colitis; Cyclams; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Female; Flavonoids; Ganglia, Spinal; Hyperalgesia; Pain Measurement; Rats; Rats, Sprague-Dawley; Receptors, CXCR4; Signal Transduction; Spinal Cord; Urinary Bladder Diseases; Urination
PubMed: 35023903
DOI: 10.2147/DDDT.S336242 -
Current Neuropharmacology 2019Three inhibitors of type-B monoamine oxidase (MAOB), selegiline, rasagiline, and safinamide, are used for the treatment of Parkinson's disease (PD). All three drugs... (Review)
Review
Three inhibitors of type-B monoamine oxidase (MAOB), selegiline, rasagiline, and safinamide, are used for the treatment of Parkinson's disease (PD). All three drugs improve motor signs of PD, and are effective in reducing motor fluctuations in patients undergoing long-term L-DOPA treatment. The effect of MAOB inhibitors on non-motor symptoms is not uniform and may not be class-related. Selegiline and rasagiline are irreversible inhibitors forming a covalent bond within the active site of MAOB. In contrast, safinamide is a reversible MAOB inhibitor, and also inhibits voltage- sensitive sodium channels and glutamate release. Safinamide is the prototype of a new generation of multi-active MAOB inhibitors, which includes the antiepileptic drug, zonisamide. Inhibition of MAOB-mediated dopamine metabolism largely accounts for the antiparkinsonian effect of the three drugs. Dopamine metabolism by MAOB generates reactive oxygen species, which contribute to nigro-striatal degeneration. Among all antiparkinsonian agents, MAOB inhibitors are those with the greatest neuroprotective potential because of inhibition of dopamine metabolism, induction of neurotrophic factors, and, in the case of safinamide, inhibition of glutamate release. The recent development of new experimental animal models that more closely mimic the progressive neurodegeneration associated with PD will allow to test the hypothesis that MAOB inhibitors may slow the progression of PD.
Topics: Alanine; Antiparkinson Agents; Benzylamines; Dopamine Agents; Humans; Indans; Levodopa; Male; Monoamine Oxidase Inhibitors; Parkinson Disease; Selegiline
PubMed: 30160213
DOI: 10.2174/1570159X16666180830100754 -
Cardiovascular Therapeutics 2008Liver X receptors (LXR) alpha and beta belong to a family of nuclear receptors which form heterodimers with the retinoid X receptor (RXR) and, upon ligand binding,... (Review)
Review
Liver X receptors (LXR) alpha and beta belong to a family of nuclear receptors which form heterodimers with the retinoid X receptor (RXR) and, upon ligand binding, stimulate the expression of target genes. LXR were initially described as orphan receptors and later oxidized cholesterol derivatives (oxysterols) were identified as their natural ligands. In addition, several synthetic LXR agonists such as T0901317 and GW3965 were synthesized. Oxysterols are formed in amounts proportional to cholesterol content in the cell and therefore LXR operate as cholesterol sensors which protect from cholesterol overload by inhibiting intestinal cholesterol absorption, stimulating cholesterol efflux from cells to high-density lipoproteins (HDL), its transport to the liver, conversion to bile acids, and biliary excretion. In addition, LXR agonists activate fatty acid synthesis by stimulating the expression of a lipogenic transcription factor, sterol regulatory element-binding protein-1c (SREBP-1c), leading to the elevation of plasma triglycerides and liver steatosis. Lipogenic effect seems is the most important negative feature of LXR agonists considered as potential hypolipidemic drugs. Some of currently used drugs also affect LXR signaling. For example, statins may impair LXR signaling by inhibiting oxysterol synthesis, whereas fibrates and thiazolidinediones increase LXR expression and activity.
Topics: Animals; Benzoates; Benzylamines; Cholesterol; DNA-Binding Proteins; Dyslipidemias; Hydrocarbons, Fluorinated; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Liver X Receptors; Orphan Nuclear Receptors; Receptors, Cytoplasmic and Nuclear; Sulfonamides
PubMed: 19035881
DOI: 10.1111/j.1755-5922.2008.00062.x -
Frontiers in Immunology 2020Our previous studies revealed a pivotal role of the chemokine stromal cell-derived factor (SDF)-1 and its receptors CXCR4 and CXCR7 on migratory behavior of...
Our previous studies revealed a pivotal role of the chemokine stromal cell-derived factor (SDF)-1 and its receptors CXCR4 and CXCR7 on migratory behavior of polymorphonuclear granulocytes (PMNs) in pulmonary inflammation. Thereby, the SDF-1-CXCR4/CXCR7-axis was linked with adenosine signaling. However, the role of the SDF-1 receptors CXCR4 and CXCR7 in acute inflammatory peritonitis and peritonitis-related sepsis still remained unknown. The presented study provides new insight on the mechanism of a selective inhibition of CXCR4 (AMD3100) and CXCR7 (CCX771) in two models of peritonitis and peritonitis-related sepsis by injection of zymosan and fecal solution. We observed an increased expression of SDF-1, CXCR4, and CXCR7 in peritoneal tissue and various organs during acute inflammatory peritonitis. Selective inhibition of CXCR4 and CXCR7 reduced PMN accumulation in the peritoneal fluid and infiltration of neutrophils in lung and liver tissue in both models. Both inhibitors had no anti-inflammatory effects in A knockout animals (A-/-). AMD3100 and CCX771 treatment reduced capillary leakage and increased formation of tight junctions as a marker for microvascular permeability in wild type animals. In contrast, both inhibitors failed to improve capillary leakage in A-/- animals, highlighting the impact of the A-receptor in SDF-1 mediated signaling. After inflammation, the CXCR4 and CXCR7 antagonist induced an enhanced expression of the protective A adenosine receptor and an increased activation of cAMP (cyclic adenosine mono phosphate) response element-binding protein (CREB), as downstream signaling pathway of A. The CXCR4- and CXCR7-inhibitor reduced the release of cytokines in wild type animals via decreased intracellular phosphorylation of ERK and NFκB p65. , CXCR4 and CXCR7 antagonism diminished the chemokine release of human cells and increased cellular integrity by enhancing the expression of tight junctions. These protective effects were linked with functional A-receptor signaling, confirming our data. In conclusion, our study revealed new protective aspects of the pharmacological modulation of the SDF-1-CXCR4/CXCR7-axis during acute peritoneal inflammation in terms of the two hallmarks PMN migration and barrier integrity. Both anti-inflammatory effects were linked with functional adenosine A-receptor signaling.
Topics: Acute Disease; Animals; Benzylamines; Capillary Permeability; Chemokine CXCL12; Cyclams; Disease Models, Animal; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophils; Peritonitis; Receptor, Adenosine A2B; Receptors, CXCR; Receptors, CXCR4; Sepsis; Signal Transduction
PubMed: 32210974
DOI: 10.3389/fimmu.2020.00407 -
Annals of Saudi Medicine 2018The safety and efficacy of dapoxetine for the treatment of premature ejaculation (PE) is still controversial. Thus, we decided to conduct a meta-analysis using trial... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The safety and efficacy of dapoxetine for the treatment of premature ejaculation (PE) is still controversial. Thus, we decided to conduct a meta-analysis using trial sequential analysis (TSA) to determine the sufficiency of conclusions.
OBJECTIVE
Evaluate the efficacy and safety of dapoxetine in the treatment of patients with PE and assess the reliability of the findings.
DESIGN
Meta-analysis of randomized controlled trials (RCTs).
METHODS
Electronic databases including PUBMED, EMBASE, Cochrane Library, CNKI and Wanfang data were reviewed up to July 2017. RCTs evaluating the efficacy of dapoxetine in patients with PE and reporting intravaginal ejaculatory latency time (IELT), patient global impression of change (PGIC) and/or adverse events (AEs) were included.
MAIN OUTCOME MEASURES
Mean differences between trials in efficacy for IELT, and risk ratios for PGIC and treatment-emergent AEs.
SAMPLE
8 RCTs.
RESULTS
For IELT and PGIC, significant effects were found for all doses of dapoxetine versus placebo, and similar results were obtained in subgroups of the 30-mg dose versus 60-mg dose. There were also statistically different dose-related effects on AEs. Trial sequential analysis showed that the result of our meta-analysis was confirmed and further trials are unnecessary.
CONCLUSIONS
The evidence suggests that dapoxetine may be a safe and effective drug for patients with PE.
REGISTRATION
Not registered, no published protocol.
CONFLICT OF INTEREST
No relationship with manufacturer of drug.
Topics: Benzylamines; Ejaculation; Humans; Male; Naphthalenes; Premature Ejaculation; Randomized Controlled Trials as Topic; Selective Serotonin Reuptake Inhibitors; Time Factors
PubMed: 30284992
DOI: 10.5144/0256-4947.2018.366 -
Pathophysiology of Haemostasis and... 2005Clinical-based evidence demonstrates that long-term oral anticoagulant therapy with the vitamin K antagonists is highly effective for the secondary prevention of venous... (Comparative Study)
Comparative Study Review
Clinical-based evidence demonstrates that long-term oral anticoagulant therapy with the vitamin K antagonists is highly effective for the secondary prevention of venous thromboembolism (VTE). However, owing to fear of bleeding complications and the inconvenience of coagulation monitoring, many patients do not receive the required duration of treatment. This can lead to a high incidence of recurrent VTE events and has prompted the evaluation of alternative treatment strategies and the development of new anticoagulants for VTE management. For patient groups in which it is particularly difficult to maintain the target intensity of anticoagulation, low-molecular-weight heparin (LMWH) has been found to significantly reduce the risk of recurrent VTE without increasing bleeding risk. The parenteral administration of LMWH, however, is a drawback for long-term use in the outpatient setting. Long-term warfarin use at a lower intensity (international normalized ratio [INR] 1.5-2.0) has also been assessed as a possible strategy to reduce bleeding complications and the need for monitoring, but results were disappointing when compared with conventional-intensity warfarin (INR 2.0-3.0). New therapies in development that may potentially offer a more favourable benefit-risk profile and greater consistency and predictability of response include the synthetic pentasaccharides, fondaparinux and idraparinux. These par enterally administered indirect factor Xa inhibitors have a predictable pharmacokinetic profile, allowing use without coagulation monitoring. Fondaparinux to date has only been evaluated in the initial treatment (5-7 days) of symptomatic deep vein thrombosis. In contrast, idraparinux, with its longer half-life (80 h) allowing once-weekly parenteral dosing, has the potential for long-term treatment and is currently being assessed in phase III trials for the secondary prevention of VTE. Currently, the most promising new therapeutic option is the first of the oral direct thrombin inhibitors, ximelagatran. The THRombin Inhibitor in VEnous thromboembolism (THRIVE) clinical trial programme has demonstrated that this agent is as effective as standard therapy for the acute treatment (THRIVE Treatment) and secondary prevention (THRIVE lll) of VTE events and is well tolerated when used for 6 months or over extended periods up to 1.5 years. Furthermore, with oral administration, fixed dosing and no requirement for anticoagulation monitoring, ximelagatran has the potential to facilitate optimal use and duration of VTE treatment by overcoming the limitations of current agents.
Topics: Anticoagulants; Azetidines; Benzylamines; Humans; Secondary Prevention; Thromboembolism; Venous Thrombosis
PubMed: 15812200
DOI: 10.1159/000083080 -
Cleveland Clinic Journal of Medicine May 2007Premature ejaculation (PE) is one of the most common sexual dysfunctions in men, with prevalence rates ranging from 21% to 31%. Because many physicians do not inquire... (Review)
Review
Premature ejaculation (PE) is one of the most common sexual dysfunctions in men, with prevalence rates ranging from 21% to 31%. Because many physicians do not inquire about sexual dysfunction and patients are reluctant to offer it as a medical complaint, PE is underreported in clinical practice. A sexual history is therefore necessary to uncover the diagnosis. PE can have a significant impact on the quality of life of the patient and his sexual partner, and may lead to psychological distress and loss of self-esteem. It appears that PE has no single etiology, and treatments have been based on both its neurophysiologic and behavioral components. Although no therapies are currently approved for PE by the US Food and Drug Administration, medications that have shown some success include selective serotonin reuptake inhibitors, tricyclic antidepressants, phosphodiesterase type 5 inhibitors, and topical anesthetics. Behavioral techniques have been the mainstay of PE treatment, and include techniques to decrease sensory input.
Topics: Administration, Topical; Anesthetics; Antidepressive Agents, Tricyclic; Benzylamines; Diagnosis, Differential; Ejaculation; Humans; Male; Medical History Taking; Naphthalenes; Risk Factors; Selective Serotonin Reuptake Inhibitors; Sex Counseling; Sexual Behavior; Sexual Dysfunction, Physiological
PubMed: 17546831
DOI: 10.3949/ccjm.74.suppl_3.s47