ABSTRACT
AIMS: To measure nurses' compliance with standard precautions during the COVID-19 pandemic, compare findings with previous assessments and describe the barriers affecting nurses' compliance. BACKGROUND: Healthcare providers' compliance with standard precautions is still limited worldwide. Implementation of infection control policies in hospitals is needed internationally, especially during a pandemic. Surprisingly, studies exploring nurses' compliance with standard precautions are lacking during COVID-19. METHODS: A multicenter cross-sectional study was adopted in two Italian hospitals. Nurses' compliance with standard precautions was measured through The Compliance with Standard Precautions Scale (Italian version). An open-ended question explored the barriers to nurses' compliance with standard precautions. Reporting, followed the STROBE guidelines. RESULTS: A total of 201 nurses were enrolled in 2020. Nurses' compliance with standard precautions was suboptimal. A statistically significant improvement in the compliance rate with standard precautions was observed between pre- and during COVID-19 assessments. High compliance was found in the appropriate use of surgical masks, gloves and sharps disposal. Nurses perceived personal, structural and organizational barriers to standard precautions adherence. CONCLUSION: Nurses' compliance with standard precautions was not 100%, and different factors impeded nurses to work safely. Our findings provide institutional leaders and educators with the basis for implementing policies to optimize nurse safety, well-being and patient care. IMPLICATIONS FOR NURSING AND HEALTH POLICIES: Nurses have the right to work safely, and when the shortage of personal protective equipment and nurses during an emergency threatens healthcare quality worldwide, policymakers are challenged to act by establishing an effective allocation of resources for consistent compliance with standard precautions. Moreover, nurses should actively engage in the implementation of infection control policies to improve safe behaviours among citizens and students accessing hospitals.
Subject(s)
COVID-19 , Nurses , Humans , Cross-Sectional Studies , Pandemics/prevention & control , COVID-19/epidemiology , Infection Control , Guideline Adherence , Surveys and QuestionnairesABSTRACT
We previously demonstrated that natural product-inspired 3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-ones derivatives delivered potent and selective PIM kinases inhibitors however with non-optimal ADME/PK properties and modest oral bioavailability. Herein, we describe a structure-based scaffold decoration and a stereoselective approach to this chemical class. The synthesis, structure-activity relationship studies, chiral analysis, and pharmacokinetic data of compounds from this inhibitor class are presented herein. Compound 20c demonstrated excellent potency on PIM1 and PIM2 with exquisite kinases selectivity and PK properties that efficiently and dose-dependently promoted c-Myc degradation and appear to be promising lead compounds for further development.
Subject(s)
Alkaloids , Antineoplastic Agents , Alkaloids/pharmacology , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-pim-1/chemistry , Proto-Oncogene Proteins c-pim-1/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
In this article we describe the identification of unprecedented ATP-competitive ChoKα inhibitors starting from initial hit NMS-P830 that binds to ChoKα in an ATP concentration-dependent manner. This result is confirmed by the co-crystal structure of NMS-P830 in complex with Δ75-ChoKα. NMS-P830 is able to inhibit ChoKα in cells resulting in the reduction of intracellular phosphocholine formation. A structure-based medicinal chemistry program resulted in the identification of selective compounds that have good biochemical activity, solubility and metabolic stability and are suitable for further optimization. The ChoKα inhibitors disclosed in this article demonstrate for the first time the possibility to inhibit ChoKα with ATP-competitive compounds.
Subject(s)
Adenosine Triphosphate/antagonists & inhibitors , Choline Kinase/antagonists & inhibitors , Cyclohexanes/pharmacology , Protein Kinase Inhibitors/pharmacology , Adenosine Triphosphate/metabolism , Choline Kinase/metabolism , Cyclohexanes/chemical synthesis , Cyclohexanes/chemistry , Dose-Response Relationship, Drug , Humans , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
Parkinson's Disease is associated with a high assistive complexity, thus generating in caregivers a burden proportional to the intensity of the care provided. This study aims to evaluate whether the stress-related level of caregivers is related to their perception of the need for healthcare education. A cross-sectional study was conducted on 69 family caregivers that completed the Stress-related Vulnerability Scale (SVS scale) with a tool of proposed interventions stratified according to caregivers' need as "nothing", "somewhat", "moderately" and "extremely". A direct association between the SVS scale and the perception of the usefulness of interventions was detected, and significant differences were observed for "Caregivers tele-support group" and "Peer-led support group" interventions, thus suggesting an important role for caregivers' emotional status in considering of training courses. Caregivers are split between low vulnerability, with minimal perception of training need, and high burden state with the acute necessity of support to manage patients.
Subject(s)
Caregivers/education , Caregivers/psychology , Family/psychology , Parkinson Disease/nursing , Parkinson Disease/psychology , Adult , Aged , Aged, 80 and over , Cross-Sectional Studies , Female , Humans , Male , Middle Aged , Stress, PsychologicalABSTRACT
Madariaga Virus (MADV) is an emergent Alphavirus of the eastern equine encephalitis virus (EEEV) strain complex causing epizootic epidemics. In this study the genetic diversity and the transmission dynamics of Madariaga virus has been investigated by Bayesian phylogenetics and phylodynamic analysis. A database of 32 sequences of MADV group structural polyprotein were downloaded from GenBank, aligned manually edited by Bioedit Software. ModelTest v. 3.7 was used to select the simplest evolutionary model that adequately fitted the sequence data. Neighbor-joining tree was generated using MEGA7. The phylogenetic signal of the dataset was tested by the likelihood mapping analysis. The Bayesian phylogenetic tree was built using BEAST. Selective pressure analysis revealed one positive selection site. The phylogenetic trees showed two main clusters. In particular, Lineage II showed an epizootic infection in monkeys and Lineage III, including 2 main clusters (IIIa and IIIB), revealing an epizootic infection in humans in Haiti and an epizootic infection in humans in Venezuela during the 2016, respectively. The Bayesian maximum clade credibility tree and the time of the most common recent ancestor estimates, showed that the root of the tree dated back to the year 346 with the probable origin in Brazil. Gene flow analysis revealed viral exchanges between different neighbor countries of South America. In conclusion, Bayesian phylogenetic and phylodynamic represent useful tools to follow the transmission dynamic of emergent pathogens to prevent new epidemics spreading worldwide.
Subject(s)
Encephalitis Virus, Eastern Equine/genetics , Encephalitis Virus, Eastern Equine/pathogenicity , Encephalomyelitis, Equine/epidemiology , Encephalomyelitis, Equine/transmission , Encephalomyelitis, Equine/virology , Phylogeny , Alphavirus Infections , Animals , Base Sequence , Bayes Theorem , Brazil , Encephalitis Virus, Eastern Equine/classification , Epidemics , Evolution, Molecular , Gene Flow , Genetic Variation , Haiti , Haplorhini , Humans , RNA, Viral/genetics , Sequence Alignment , South America , VenezuelaABSTRACT
Aim To explore factors that influence intensive care nurses' experiences of being compliant with standard precautions (SP) during emergencies. BACKGROUND: Intensive care nurses can be exposed to a greater risk of biohazardous exposure during an emergency. The primary strategy to address the complex variety of biological hazards in clinical practice is represented by the implementation of SP guidelines. Previous research has indicated that nurses' compliance rates with SPs are suboptimal, but no study has focused on the factors influencing compliance during an emergency. DESIGN: A descriptive qualitative study was conducted in an Italian university hospital with 19 intensive care nurses who had at least two years of work experience in critical care. The nurses were interviewed in four focus groups and were asked about their experiences of being compliant with SPs during an emergency. Data were analyzed using conventional content analysis. RESULTS: Three themes emerged: conflict, competencies, and context. Conflict was reported regarding the need to save the patient and the need for self-protection through the use of SPs. In particular, nurses had to manage the pressure of limited time. Competencies were identified by nurses' knowledge, attitude, skills, training, and experience. Context was related to the work and organizational conditions during the emergency, including overcrowding. CONCLUSION: To support intensive care nurses' compliance with SPs during emergencies, conflict, competencies, and context should be audited regularly in clinical practice. The findings of this study could inform infection control programs and training that targets intensive care nurses.
Subject(s)
Emergency Medical Services/standards , Guideline Adherence , Intensive Care Units , Nursing Staff, Hospital , Adult , Female , Humans , Infection Control/standards , Male , Middle Aged , Occupational Health , Qualitative ResearchABSTRACT
Chronic diseases are mostly managed by family caregivers that often face the "caregiver burden". This study aimed to understand whether a multidisciplinary theoretical-practical training course could influence the burden, health literacy and needs of caregivers. Seventy-six familial caregivers were asked to complete the Caregiver Burden Inventory-CBI, Caregiver Needs Assessment-CNA, and Health Literacy Questionnaire-HLQ, before and after the course. A significant decrease in CBI and an increase of CNA were observed. However, a significantly higher rate of CBI decrease and a lower increase of CNA were detected in the neurological compared to the oncological group (pâ¯=â¯0.001). Moreover, the ability of the participants to look for and find health information significantly improved. The course contrasted caregivers' burden, increased their search for health information, and revealed their requiring of training and emotional and social support. Caregiver education plays a pivotal role in the management of chronic patients, enhancing the quality of life of both patients and caregivers.
Subject(s)
Adaptation, Psychological , Caregivers/education , Caregivers/psychology , Chronic Disease/psychology , Family/psychology , Health Literacy , Quality of Life/psychology , Adult , Aged , Aged, 80 and over , Humans , Male , Middle Aged , Surveys and Questionnaires , Young AdultABSTRACT
Two small-molecule-drug conjugates (SMDCs, 6 and 7) featuring lysosomally cleavable linkers (namely the Val-Ala and Phe-Lys peptide sequences) were synthesized by conjugation of the αvß3-integrin ligand cyclo[DKP-RGD]-CH2NH2 (2) to the anticancer drug paclitaxel (PTX). A third cyclo[DKP-RGD]-PTX conjugate with a nonpeptide "uncleavable" linker (8) was also synthesized to be tested as a negative control. These three SMDCs were able to inhibit biotinylated vitronectin binding to the purified αVß3-integrin receptor at nanomolar concentrations and showed good stability at pHâ 7.4 and pHâ 5.5. Cleavage of the two peptide linkers was observed in the presence of lysosomal enzymes, whereas conjugate 8, which possesses a nonpeptide "uncleavable" linker, remained intact under these conditions. The antiproliferative activities of the conjugates were evaluated against two isogenic cell lines expressing the integrin receptor at different levels: the acute lymphoblastic leukemia cell line CCRF-CEM (αVß3-) and its subclone CCRF-CEM αVß3 (αVß3+). Fairly effective integrin targeting was displayed by the cyclo[DKP-RGD]-Val-Ala-PTX conjugate (6), which was found to differentially inhibit proliferation in antigen-positive CCRF-CEM αVß3 versus antigen-negative isogenic CCRF-CEM cells. The total lack of activity displayed by the "uncleavable" cyclo[DKP-RGD]-PTX conjugate (8) clearly demonstrates the importance of the peptide linker for achieving the selective release of the cytotoxic payload.
Subject(s)
Antineoplastic Agents/chemical synthesis , Diketopiperazines/chemistry , Lysosomes/chemistry , Oligopeptides/chemistry , Paclitaxel/analogs & derivatives , Peptides, Cyclic/chemical synthesis , Peptidomimetics/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Binding, Competitive , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Liberation , Drug Stability , Humans , Integrin alphaVbeta3/metabolism , Ligands , Molecular Structure , Paclitaxel/chemical synthesis , Paclitaxel/chemistry , Paclitaxel/pharmacology , Peptides, Cyclic/chemistry , Peptides, Cyclic/pharmacology , Peptidomimetics/chemistry , Peptidomimetics/pharmacologyABSTRACT
VCP (also known as p97 or Cdc48p in yeast) is an AAA(+) ATPase regulating endoplasmic reticulum-associated degradation. After high-throughput screening, we developed compounds that inhibit VCP via different mechanisms, including covalent modification of an active site cysteine and a new allosteric mechanism. Using photoaffinity labeling, structural analysis and mutagenesis, we mapped the binding site of allosteric inhibitors to a region spanning the D1 and D2 domains of adjacent protomers encompassing elements important for nucleotide-state sensing and ATP hydrolysis. These compounds induced an increased affinity for nucleotides. Interference with nucleotide turnover in individual subunits and distortion of interprotomer communication cooperated to impair VCP enzymatic activity. Chemical expansion of this allosteric class identified NMS-873, the most potent and specific VCP inhibitor described to date, which activated the unfolded protein response, interfered with autophagy and induced cancer cell death. The consistent pattern of cancer cell killing by covalent and allosteric inhibitors provided critical validation of VCP as a cancer target.
Subject(s)
Acetanilides/pharmacology , Adenosine Triphosphatases/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Benzothiazoles/pharmacology , Cell Cycle Proteins/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Neoplasms/drug therapy , Neoplasms/pathology , Acetanilides/chemistry , Adenosine Triphosphatases/metabolism , Allosteric Regulation/drug effects , Antineoplastic Agents/chemistry , Benzothiazoles/chemistry , Cell Cycle Proteins/metabolism , Cell Death/drug effects , Cell Line, Tumor , Enzyme Inhibitors/chemistry , Humans , Models, Molecular , Molecular Structure , Neoplasms/metabolism , Structure-Activity Relationship , Valosin Containing ProteinABSTRACT
Compound 1, a hit from the screening of our chemical collection displaying activity against JAK2, was deconstructed for SAR analysis into three regions, which were explored. A series of compounds was synthesized leading to the identification of the potent and orally bioavailable JAK2 inhibitor 16 (NMS-P830), which showed an encouraging tumour growth inhibition in SET-2 xenograft tumour model, with evidence for JAK2 pathway suppression demonstrated by in vivo pharmacodynamic effects.
Subject(s)
Amides/chemical synthesis , Antineoplastic Agents/chemical synthesis , Janus Kinase 2/antagonists & inhibitors , Leukemia, Megakaryoblastic, Acute/drug therapy , Protein Kinase Inhibitors/chemical synthesis , Pyrroles/chemical synthesis , Amides/pharmacology , Animals , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Female , Gene Expression , High-Throughput Screening Assays , Humans , Janus Kinase 2/chemistry , Janus Kinase 2/genetics , Janus Kinase 2/metabolism , Leukemia, Megakaryoblastic, Acute/enzymology , Leukemia, Megakaryoblastic, Acute/genetics , Leukemia, Megakaryoblastic, Acute/pathology , Megakaryocyte Progenitor Cells/drug effects , Megakaryocyte Progenitor Cells/enzymology , Megakaryocyte Progenitor Cells/pathology , Mice , Mice, Nude , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Kinase Inhibitors/pharmacology , Pyrroles/pharmacology , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
We report herein the discovery, structure guided design, synthesis and biological evaluation of a novel class of JAK2 inhibitors. Optimization of the series led to the identification of the potent and orally bioavailable JAK2 inhibitor 28 (NMS-P953). Compound 28 displayed significant tumour growth inhibition in SET-2 xenograft tumour model, with a mechanism of action confirmed in vivo by typical modulation of known biomarkers, and with a favourable pharmacokinetic and safety profile.
Subject(s)
Antineoplastic Agents/pharmacology , Janus Kinase 2/antagonists & inhibitors , Neoplasms, Experimental/drug therapy , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Pyrroles/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Janus Kinase 2/metabolism , Mice , Mice, SCID , Models, Molecular , Molecular Structure , Neoplasms, Experimental/pathology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Pyrroles/chemical synthesis , Pyrroles/chemistry , Structure-Activity Relationship , Substrate SpecificityABSTRACT
BACKGROUND: Scant data are available on the link between armed conflicts and the development and spread of antimicrobial resistance. OBJECTIVES: We performed a systematic review with the aim to summarize the available data on the prevalence and features of antibiotic resistance and the causes of antibiotic resistance development during armed conflicts in the 21st century. METHODS: Data sources: PubMed and SCOPUS databases were searched from 1 January 2000 to 30 November 2023. STUDY ELIGIBILITY CRITERIA: Original articles reporting data on armed conflicts and antimicrobial resistance were included in this systematic review. No attempt was made to obtain information from unpublished studies. No language restriction was applied. Methods of data synthesis: Both quantitative and qualitative information were summarized by means of textual descriptions. PARTICIPANTS: Patients or soldiers deployed in armed conflict zones. TESTS: culture-dependent antibiotic sensitivity testing or molecular detection of the genetic determinants of antibiotic resistance after a confirmed diagnosis of bacterial infection. Assessment of risk of bias: To evaluate the quality of the included studies, we adapted the tool recommended by the Joanna Briggs Institute. RESULTS: Thirty-four studies were identified, published between November 2004 and November 2023. The quality of included studies was high and medium in 47% and 53% of the studies, respectively. The included studies reported high infection and colonization rates of multidrug-resistant bacteria. Studies performed during the Eastern Ukraine conflict reported high rates of New Delhi metallo-ß-lactamase producers. DISCUSSION: Our findings confirm that wars lead to a large pool of multidrug-resistant infections that could potentially spread. Infection control in healthcare facilities in conflict zones and proper antimicrobial stewardship are crucial.
Subject(s)
Anti-Bacterial Agents , Armed Conflicts , Humans , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Drug Resistance, Bacterial , Bacterial Infections/microbiology , Bacterial Infections/epidemiology , Bacterial Infections/drug therapy , Microbial Sensitivity Tests , Global Health , Prevalence , Bacteria/drug effects , Bacteria/genetics , Bacteria/isolation & purificationABSTRACT
A novel series of PIM inhibitors was derived from a combined effort in natural product-inspired library generation and screening. The novel pyrrolo[1,2-a]pyrazinones initial hits are inhibitors of PIM isoforms with IC50 values in the low micromolar range. The application of a rational optimization strategy, guided by the determination of the crystal structure of the complex in the kinase domain of PIM1 with compound 1, led to the discovery of compound 15a, which is a potent PIM kinases inhibitor exhibiting excellent selectivity against a large panel of kinases, representative of each family. The synthesis, structure-activity relationship studies, and pharmacokinetic data of compounds from this inhibitor class are presented herein. Furthermore, the cellular activities including inhibition of cell growth and modulation of downstream targets are also described.
Subject(s)
Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Pyrazines/chemistry , Pyrazines/pharmacology , Drug Discovery , Humans , Molecular Docking Simulation , Protein Kinase Inhibitors/chemical synthesis , Protein Structure, Tertiary , Proto-Oncogene Proteins c-pim-1/chemistry , Proto-Oncogene Proteins c-pim-1/metabolism , Pyrazines/chemical synthesisABSTRACT
Novel small molecule inhibitors of heat shock protein 90 (Hsp90) were discovered with the help of a fragment based drug discovery approach (FBDD) and subsequent optimization with a combination of structure guided design, parallel synthesis and application of medicinal chemistry principles. These efforts led to the identification of compound 18 (NMS-E973), which displayed significant efficacy in a human ovarian A2780 xenograft tumor model, with a mechanism of action confirmed in vivo by typical modulation of known Hsp90 client proteins, and with a favorable pharmacokinetic and safety profile.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Isoxazoles/chemistry , Isoxazoles/pharmacology , Animals , Antineoplastic Agents/therapeutic use , Binding Sites , Biomarkers, Tumor/metabolism , Catalytic Domain , Cell Line, Tumor , Cell Survival/drug effects , Crystallography, X-Ray , Drug Design , Drug Evaluation, Preclinical , Female , HSP90 Heat-Shock Proteins/metabolism , Humans , Isoxazoles/therapeutic use , Mice , Mice, Inbred BALB C , Mice, Nude , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , Protein Binding/drug effects , Structure-Activity Relationship , Transplantation, HeterologousABSTRACT
BACKGROUND: Monitoring antibody response following SARS-CoV-2 vaccination is strategic, and neutralizing antibodies represent the gold standard. The neutralizing response to Beta and Omicron VOCs was evaluated versus the gold standard by a new commercial automated assay. METHODS: Serum samples from 100 healthcare workers from the Fondazione Policlinico Universitario Campus Biomedico and the Pescara Hospital were collected. IgG levels were determined by chemiluminescent immunoassay (Abbott Laboratories, Wiesbaden, Germany) and serum neutralization assay as the gold standard. Moreover, a new commercial immunoassay, the PETIA test Nab (SGM, Rome, Italy), was used for neutralization evaluation. Statistical analysis was performed with R software, version 3.6.0. RESULTS: Anti-SARS-CoV-2 IgG titers decayed during the first ninety days after the vaccine second dose. The following booster dose significantly (p < 0.001) increased IgG levels. A correlation between IgG expression and neutralizing activity modulation was found with a significant increase after the second and the third booster dose (p < 0.05. Compared to the Beta variant of the virus, the Omicron VOC was associated with a significantly larger quantity of IgG antibodies needed to achieve the same degree of neutralization. The best Nab test cutoff for high neutralization titer (≥1:80) was set for both Beta and Omicron variants. CONCLUSION: This study correlates vaccine-induced IgG expression and neutralizing activity using a new PETIA assay, suggesting its usefulness for SARS-CoV2 infection management.
ABSTRACT
The synthesis and SAR of a series of novel pyrazolo-quinazolines as potent and selective MPS1 inhibitors are reported. We describe the optimization of the initial hit, identified by screening the internal library collection, into an orally available, potent and selective MPS1 inhibitor.
Subject(s)
Amides/chemistry , Cell Cycle Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Quinazolines/chemistry , Administration, Oral , Amides/chemical synthesis , Amides/pharmacokinetics , Animals , Cell Cycle Proteins/metabolism , Mice , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Protein Serine-Threonine Kinases/metabolism , Protein-Tyrosine Kinases , Structure-Activity RelationshipABSTRACT
The introduction of the isoxazole ring as bioisosteric replacement of the acetyl group of anatoxin-a led to a new series of derivatives binding to nicotinic acetylcholine receptors. Bulkier substitutions than methyl at the 3 position of isoxazole were shown to be detrimental for the activity. The binding potency of the most interesting compounds with α1, α7 and α3ß4 receptor subtypes, was, anyway, only at micromolar level. Moreover, differently from known derivatives with pyridine, isoxazole condensed to azabicyclo ring led to no activity.
Subject(s)
Receptors, Nicotinic/metabolism , Tropanes/chemistry , Chemistry Techniques, Synthetic , Cyanobacteria Toxins , Dose-Response Relationship, Drug , Ligands , Molecular Conformation , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The hypothalamic peptides orexin-A and orexin-B are potent agonists of two G-protein coupled receptors, namely the OX(1) and the OX(2) receptor. These receptors are widely distributed, though differentially, in the rat brain. In particular, the OX(1) receptor is highly expressed throughout the hypothalamus, whilst the OX(2) receptor is mainly located in the ventral posterior nucleus. A large body of compelling evidence, both pre-clinical and clinical, suggests that the orexin system is profoundly implicated in sleep disorders. In particular, modulation of the orexin receptors activation by appropriate antagonists was proven to be an efficacious strategy for the treatment of insomnia in man. A novel, drug-like bis-amido piperidine derivative was identified as potent dual OX(1) and OX(2) receptor antagonists, highly effective in a pre-clinical model of sleep.
Subject(s)
Drug Discovery , Piperidines/pharmacology , Receptors, G-Protein-Coupled/antagonists & inhibitors , Receptors, Neuropeptide/antagonists & inhibitors , Sleep Wake Disorders/drug therapy , Animals , Crystallography, X-Ray , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Orexin Receptors , Piperidines/chemical synthesis , Piperidines/chemistry , Rats , Receptors, G-Protein-Coupled/metabolism , Receptors, Neuropeptide/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
This article deals with the synthesis and the activities of some 1,5-dialkyl-3-arylureido-1,5-benzodiazepin-2,4-diones which were prepared as potential CCK2 antagonists, with the intention to find a possible follow up of our lead compound GV150013, showing an improved pharmacokinetic profile. The phenyl ring at N-5 was replaced with more hydrophilic substituents, like alkyl groups bearing basic functions. In some cases, the resolution of the racemic key intermediates 3-amino-benzodiazepines was also accomplished. Among the compounds synthesized and characterised so far in this class, the 5-morpholinoethyl derivative 54, was selected as potential follow up of GV150013 and submitted for further evaluation.
Subject(s)
Benzodiazepinones/pharmacology , Receptor, Cholecystokinin B/antagonists & inhibitors , Animals , Benzodiazepinones/chemical synthesis , Benzodiazepinones/chemistry , Dogs , Guinea Pigs , Mice , Molecular Structure , Rats , Stereoisomerism , Structure-Activity Relationship , Tissue DistributionABSTRACT
A new class of azabicyclo[3.1.0]benzenesulfonamides is presented as selective dopamine D3 antagonists together with SAR and selectivity data.