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1.
Radiography (Lond) ; 30(1): 319-331, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38128248

ABSTRACT

OBJECTIVES: Using a narrative approach, this paper aims to determine the extent of Australian radiographers' regulatory compliance to improve patient safety when performing appendicular X-ray and non-contrast brain computed tomography (CT) in the Emergency Department (ED). KEY FINDINGS: A narrative review explored relevant literature and key regulatory policy. Ten documents were identified, three main themes were developed related to the radiographer roles in X-ray request justification, dose optimisation and preliminary image evaluation (PIE). Radiographers were equally aware of justification and optimisation pre and post the introduction of a Medical Code of Practice. The collective PIE accuracy of radiographers remained unaffected by changes in mode of PIE delivery and regulatory factors but varied based on the anatomical region. CONCLUSION: While current Australian regulations mandate radiographer request justification, dose optimisation and PIE, the degree of compliance by Australian radiographers remains uncertain. Current literature provides evidence that radiographers can improve patient care and safety through justification, optimisation, and PIE delivery. Change in workplace practice, supported by key stakeholders including radiologists, is essential to integrate radiographers' functions into routine ED clinical practice. Further research is required to audit radiographers' regulatory compliance to improve patient safety. IMPLICATIONS FOR PRACTICE: Patient safety in ED can be improved with timely and accurate diagnosis provided by radiographers. Radiographers have a professional obligation to adhere to the capabilities and standards for safe medical radiation practice defined by Australian regulations. Therefore, radiographers must justify the X-ray request, optimise the radiation dose where appropriate and communicate urgent or unexpected findings to the referrer.


Subject(s)
Patient Safety , Radiologists , Humans , Australia , Radiography , Emergency Service, Hospital
2.
Med Educ ; 2023 Dec 11.
Article in English | MEDLINE | ID: mdl-38073499

ABSTRACT

CONTEXT: Realist evaluation is increasingly employed in health professions education research (HPER) because it can unpack the extent to which complex educational interventions work (or not), for whom under what circumstances and how. While realist evaluation is not wedded to particular methods, realist interviews are commonly the primary, if not only, data collection method in realist evaluations. While qualitative interviewing from an interpretivist standpoint has been well-articulated in the HPER literature, realist interviewing differs substantially. The former elicits participants' views and experiences of a topic of inquiry, whereas realist interviewing focuses on building, testing and/or refining programme theory. Therefore, this article aims to help readers better understand, conduct, report and critique realist interviews as part of realist evaluations. METHODS: In this paper, we describe what realist approaches are, what realist interviewing is and why realist interviewing matters. We outline five stages to realist interviewing (developing initial programme theory, realist sampling/samples, the interview itself, realist analysis and reporting realist interviews), drawing on two illustrative cases from our own realist evaluations employing interviewing to bring theory to life. We provide a critical analysis of 12 realist evaluations employing interviewing in the HPER literature. Alongside reporting standards, and our own realist interviewing experiences, this critical analysis of published articles serves to foreground our recommendations for realist interviewing. CONCLUSIONS: We encourage HPE researchers to consider realist interviews as part of realist evaluations of complex interventions. Our critical analysis reveals that realist interviews can provide unique insights into HPE, but authors now need to report their sampling approach, type of interviewing and interview questions more explicitly. Studies should also more explicitly draw on existing realist interviewing literature and follow reporting guidelines for realist evaluations. We hope this paper provides a useful roadmap to conducting, reporting and critically appraising realist interviews in HPER.

3.
Nurs Open ; 10(8): 5462-5475, 2023 08.
Article in English | MEDLINE | ID: mdl-37141515

ABSTRACT

AIM: This article aimed to provide a snapshot of demographics and professional characteristics of nursing and midwifery workforce in Australian primary health care (PHC) settings during 2015-2019 and factors that influenced their decisions to work in PHC. DESIGN: Longitudinal retrospective survey. METHODS: Longitudinal data that were collected from a descriptive workforce survey were retrieved retrospectively. After collation and cleaning, data from 7066 participants were analysed using descriptive and inferential statistics in SPSS version 27.0. RESULTS: The majority of the participants were female, aged between 45 and 64 years old and working in general practice. There was a small yet steady increase in the number of participants in the 25-34 age group and a downward trend in the percentage of postgraduate study completion among participants. While factors perceived most/least important to their decision to work in PHC were consistent during 2015-2019, these factors differed among different age groups and postgraduate qualification holders. This study's findings are both novel and supported by previous research. It is necessary to tailor recruitment and retention strategies to nurses/midwives' age groups and qualifications to attract and retain highly skilled and qualified nursing and midwifery workforce in PHC settings.


Subject(s)
Midwifery , Pregnancy , Humans , Male , Female , Middle Aged , Australia , Retrospective Studies , Workforce , Primary Health Care
4.
Med Teach ; 44(9): 977-985, 2022 09.
Article in English | MEDLINE | ID: mdl-35382670

ABSTRACT

PURPOSE: While online learning for faculty development has grown substantially over recent decades, it has been further accelerated in the face of the worldwide pandemic. The effectiveness of online learning has been repeatedly established through systematic reviews and meta-analyses, yet questions remain about its cost-effectiveness. This study evaluates how synchronous online supervision training workshops and their cost-effectiveness might work, and in what contexts. METHODS: We conducted preliminary realist economic evaluation including qualitative (13 realist interviews), and quantitative approaches (cost Ingredients method). We developed a cost-optimised model based on identified costs and cost-sensitive mechanisms. RESULTS: We identified 14 recurring patterns (so-called demi-regularities) illustrating multiple online workshop outcomes (e.g. satisfaction, engagement, knowledge), generated by various mechanisms (e.g. online technology, mixed pedagogies involving didactic and active/experiential learning, peer learning), and triggered by two contexts (supervisor experience levels, and workplace location). Each workshop cost $302.92 per learner, but the optimised model including senior facilitators cost $305.70. CONCLUSIONS: Our initial realist program theories were largely supported and refined. Although findings were largely concordant with previous literature, we illustrate how online workshop costs compare favourably with face-to-face alternatives. We encourage program developers to consider synchronous online learning for faculty development especially for remote learners, and in resource-constrained environments.


Subject(s)
Education, Distance , Cost-Benefit Analysis , Faculty , Humans , Research Design , Workplace
5.
Acad Med ; 97(8): 1203-1212, 2022 08 01.
Article in English | MEDLINE | ID: mdl-35385398

ABSTRACT

PURPOSE: Supervision training supports health care supervisors to perform their essential functions. Realist evaluations are increasingly popular for evaluating complex educational interventions, but no such evaluations exist appraising supervision workshops. Building on an earlier realist synthesis of supervision training, the authors evaluated whether supervision workshops work, for whom and under what circumstances, and why. METHOD: The authors conducted a 2-stage realist evaluation during 2018-2019 to refine and develop program theory. The intervention involved half-day, face-to-face supervision workshops as part of an Australian state-wide government-funded program for health care and human services supervisors. Data collection involved realist interviews with 10 workshop developers (stage 1) and 43 supervisors (stage 2). The authors employed team-based data analysis using realist logic to refine and develop program theory by identifying contexts, mechanisms, outcomes, and context-mechanism-outcome configurations. RESULTS: Despite their brevity, the supervision workshops had many reported benefits for supervisors (e.g., improved satisfaction) through various perceived mechanisms pertaining to pedagogy (e.g., mixed pedagogies), workshops (e.g., optimal duration), and individuals (e.g., supervisor engagement). However, they also yielded negative reported outcomes (e.g., suboptimal knowledge gains) brought about by assorted perceived mechanisms related to pedagogy (e.g., suboptimal peer learning), workshops (e.g., content irrelevance), and individuals (e.g., suboptimal facilitator competence). Such mechanisms were thought to be triggered by diverse contexts including supervisors' levels of experience, sector, and workplace supervision cultures. CONCLUSIONS: While the findings partly support the realist synthesis of supervision training and previous realist evaluations of faculty development, this realist evaluation extends this literature considerably. Health care educators should employ mixed pedagogies (e.g., didactic teaching, peer learning), relevant content, optimal workshop duration, and competent/engaging facilitators. Educators also need to tailor workshops according to supervisors' contexts including the sectors and supervision cultures in which supervision is practiced, and supervisors' levels of experience (e.g., experienced supervisors appreciated workshop brevity).


Subject(s)
Personnel Management , Australia , Clinical Competence , Humans , Personal Satisfaction , Workplace
6.
Nurse Educ Today ; 110: 105225, 2022 Mar.
Article in English | MEDLINE | ID: mdl-35344840

ABSTRACT

BACKGROUND: Training helps maintain high-quality supervision and its associated benefits (e.g. reduced burnout, improved care). While studies have previously evaluated extended-duration supervision training programmes, none have treated these as complex interventions so have not employed realist approaches. OBJECTIVES: Building on a previous realist synthesis, this evaluation tests and develops programme theory for extended-duration supervision training to answer the question: to what extent does the supervision training programme work, for whom, under what circumstances and why? DESIGN: We conducted a realist evaluation of a novel state-wide Victorian 3-month supervision training programme including one or two 3.5-h workshops followed by weekly reflexive longitudinal audio diaries (LADs) for up to 12 weeks. METHODS: Realist evaluation data comprised 25 entrance interviews with nurses and allied health professionals, 176 LADs (and 29 written diaries), and 23 exit interviews. We employed team-based realist analysis to identify context-mechanism-outcome configurations (CMOCs) to test and develop programme theory. RESULTS: We refined four recurring CMOCs from the realist synthesis programme theory, found insufficient evidence for two, and established five new recurring CMOCs. We identified multiple positive outcomes from our extended-duration supervision training programme (e.g. improved supervisor practices) through various mechanisms relating to pedagogy (e.g. weekly reflexivity), supervisors (e.g. engagement), and workplaces (e.g. enabling supervision cultures). Some negative outcomes were reported (e.g. decreased engagement) through various mechanisms (e.g. suboptimal training design). Such mechanisms were thought to come about by diverse contexts including supervisors (e.g. inexperienced/experienced), professions (nursing/allied health), and organisations (supervision-enabled/non-enabled cultures). CONCLUSIONS: Our findings extend the realist synthesis programme theory by highlighting various contexts triggering outcome-generating mechanisms. Programme outcomes are maximised through ongoing supervisor reflexivity paying attention to facilitator-supervisor relationships, as well as protected time for supervisors to translate learning into practice.


Subject(s)
Allied Health Personnel , Workplace , Humans , Learning
7.
Med Educ ; 56(4): 407-417, 2022 Apr.
Article in English | MEDLINE | ID: mdl-34817093

ABSTRACT

INTRODUCTION: Cost studies are increasingly popular given resource constraints. While scholars stress the context-dependent nature of cost, and the importance of theory, cost studies remain context-blind and atheoretical. However, realist economic evaluation (REE) privileges context and the testing/refinement of economic programme theory. This preliminary REE serves to test and refine economic programme theory for supervision training programmes of different durations to better inform future programme design/implementation. METHODS: Our preliminary REE unpacked how short (half-day) and extended (12 week) supervision training programmes in Victoria, Australia, produced costs and outcomes. We employed mixed methods: qualitative realist and quantitative cost methods. Economically optimised programme models were developed guided by identified cost-sensitive mechanisms and contexts. RESULTS: As part of identified context-mechanism-outcome configurations (CMOCs) for both training programmes, we found a wider diversity of positive outcomes but greater costs for the extended programme (11 outcomes; AU$3069/learner) compared with the short programme (7 outcomes; $385/learner). We identified four shared cost-sensitive mechanisms for both programmes (training duration, learner protected time, learner engagement, and facilitator competence) and one shared cost-sensitive context (learners' supervisory experience). We developed two economically optimised programme models: (1) short programme for experienced supervisors facilitated by senior educators ($406/learner); and (2) extended programme for inexperienced supervisors facilitated by junior educators ($2104/learner). DISCUSSION: Our initial economic programme theory was somewhat supported, refuted and refined. Results were partly consistent with previous research, but also extended it through unpacking cost-sensitive mechanisms and contexts. Although our preliminary REE fills a pressing gap in the methodology literature, conducting REE was challenging given our desire to integrate economic and realist analyses fully, and remain faithful to realist principles. Attention to training duration and experience levels of the facilitator-learner dyad may help to balance the cost and outcomes of training programmes.


Subject(s)
Cost-Benefit Analysis , Humans , Victoria
8.
Nurse Educ Today ; 90: 104438, 2020 Apr 17.
Article in English | MEDLINE | ID: mdl-32417527

ABSTRACT

OBJECTIVES: To examine the effectiveness of partnership models in clinical nursing education with regards to cost effectiveness; student employability, work-readiness, confidence, and competence; and stakeholders' satisfaction. DESIGN: Scoping review. DATA SOURCES: Research studies published in English were searched electronically through EbscoHost (CINAHL and ERIC), Scopus, Medline (via Ovid), ProQuest Central, and Web of Science databases. Criteria were developed to guide the selection of original studies published in English before 2019 for review. REVIEW METHODS: Arksey and Malley's framework (2005) and relevant enhancements guided the conduct of the review. An informal appraisal of selected studies was applied. RESULTS: Two theses and 31 articles with a variation in methodologies, methods, sample sizes, research populations and quality of evidence were included for review. Four themes were identified: (i) Description of partnership models in clinical education, (ii) length of model implementation prior to evaluation, (iii) positive qualitative findings, and (iv) quantitative findings limited by data collection periods and methods. CONCLUSIONS: Shared among the reviewed studies is stakeholder view of the positive impacts of partnership models on the clinical learning environment, and the increased level of support and individualised instruction for students. However, the use of not fully validated survey instruments and the lack of description about the implementation period before evaluation in many reviewed studies limit the interpretation of quantifiable effect of the partnership models. This review identifies a lack of attention on student employability, work-readiness, cost evaluation, patient perspective, and partnership models in low-income countries. Future research to address these knowledge gaps using high quality data collection methods and rigorous research design is warranted.

9.
Front Plant Sci ; 9: 960, 2018.
Article in English | MEDLINE | ID: mdl-30131812

ABSTRACT

The importance of the cuticular layer in regulating a plant's water status and providing protection from environmental challenges has been recognized for a long time. The cuticular layer in plants restricts non-stomatal water loss and protects plants against damage from pathogen infection and UV radiation. Much genetic and biochemical research has been done about cutin and wax transportation in Arabidopsis thaliana, but little is known about it in rice. Here, we report that a rice ATP-binding cassette (ABC) transporter, OsABCG9, is essential for normal development during vegetative growth and could play a critical role in the transportation of epicuticular wax in rice. Rice phenotypes with mutated OsABCG9 exhibited growth retardation and sensitivity to low humidity. The total amount of cuticular wax on the leaves of the osabcg9-1 mutant diminished by 53% compared with the wild type, and wax crystals disappeared completely in osabcg9-2 mutant leaves. However, OsABCG9 does not seem to be involved in cutin transportation, even though its ortholog in Arabidopsis, AtABCG11, transports both wax and cutin. Furthermore, the osabcg9-1 mutant had increased leaf chlorophyll leaching and more severe drought susceptibility. This study provides new insights about differences between rice and A. thaliana in wax and cutin transportation associated with the ABCG family during evolution.

10.
J Adv Nurs ; 74(10): 2351-2362, 2018 Oct.
Article in English | MEDLINE | ID: mdl-29893505

ABSTRACT

AIMS: To describe how clinical nurse educators (CliNEs) in Vietnam are prepared for their role; to identify which preparation strategies assist development of confidence in clinical teaching; and to measure the effect of educational qualifications and professional background on perceived confidence levels. BACKGROUND: The quality of clinical teaching can directly affect the quality of the student learning experience. The role of the clinical educator is complex and dynamic and requires a period of adjustment for successful role transition to occur. Planned orientation and specific preparation programmes assist transition and reduce anxiety for new CliNEs. There is, however, a lack of clear evidence to identify the form this preparation should take or which strategies are likely to facilitate the development of role confidence. DESIGN: Descriptive survey study. METHODS: Cross-sectional surveys were used to collect data from 334 CliNEs during January-March 2015. RESULTS: Eight preparation methods commonly used in Vietnam were identified. There was a small yet significant association between preparation and CliNEs' perceived confidence. Formal preparation methods, and postgraduate qualifications and years of clinical teaching experience were linked to increased confidence in clinical teaching. Conversely, informal mentorship was found to hinder confidence development. CONCLUSIONS: This study identifies several preparation strategies that significantly enhance clinical educator confidence and readiness for their complex role. These preparation strategies drawn from the Vietnamese context, provide important examples for the wider nursing community to consider.


Subject(s)
Faculty, Nursing/psychology , Professional Competence , Teacher Training/methods , Adult , Anxiety , Cross-Sectional Studies , Educational Status , Female , Humans , Male , Mentors , Middle Aged , Nurse's Role , Reproducibility of Results , Vietnam , Young Adult
11.
Nurs Health Sci ; 19(4): 498-508, 2017 Dec.
Article in English | MEDLINE | ID: mdl-28984409

ABSTRACT

Teaching nursing in clinical environments is considered complex and multi-faceted. Little is known about the role of the clinical nurse educator, specifically the challenges related to transition from clinician, or in some cases, from newly-graduated nurse to that of clinical nurse educator, as occurs in developing countries. Confidence in the clinical educator role has been associated with successful transition and the development of role competence. There is currently no valid and reliable instrument to measure clinical nurse educator confidence. This study was conducted to develop and psychometrically test an instrument to measure perceived confidence among clinical nurse educators. A multi-phase, multi-setting survey design was used. A total of 468 surveys were distributed, and 363 were returned. Data were analyzed using exploratory and confirmatory factor analyses. The instrument was successfully tested and modified in phase 1, and factorial validity was subsequently confirmed in phase 2. There was strong evidence of internal consistency, reliability, content, and convergent validity of the Clinical Nurse Educator Skill Acquisition Assessment instrument. The resulting instrument is applicable in similar contexts due to its rigorous development and validation process.


Subject(s)
Faculty, Nursing/psychology , Perception , Preceptorship , Psychometrics/standards , Self Efficacy , Adult , Clinical Competence/standards , Faculty, Nursing/standards , Female , Humans , Male , Psychometrics/instrumentation , Reproducibility of Results , Surveys and Questionnaires , Workforce
12.
J Org Chem ; 82(19): 10376-10387, 2017 10 06.
Article in English | MEDLINE | ID: mdl-28877441

ABSTRACT

An efficient large-scale synthesis of acid 1, a penultimate precursor to the HCV NS5A inhibitor BMS-986097, along with the final API step are described. Three routes were devised for the synthesis of 1 at the various stages of the program. The third generation route, the one that proved scalable and is the main subject of this paper, features a one-step Michael addition of t-butyl 2-((diphenylmethylene)amino)acetate (24) to (E)-benzyl 4-(1-hydroxycyclopropyl)but-2-enoate (28) followed by cyclization and chiral separation to form 27c, the core skeleton of cap piece 1. The epimerization and chiral resolution of 27c followed by further synthetic manipulations involving the carbamate formation, lactone reduction and cyclization, afforded cyclopropyl pyran 1. A detailed study of diphenylmethane deprotection via acid hydrolysis as well as a key lactone to tetrahydropyran conversion, in order to avoid a side reaction that afforded an alternative cyclization product, are discussed. This synthesis was applied to the preparation of more than 100 g of the final API BMS-986097 for toxicology studies.


Subject(s)
Antiviral Agents/chemical synthesis , Glycine/analogs & derivatives , Imidazoles/chemical synthesis , Pyrans/pharmacology , Pyrrolidines/chemical synthesis , Spiro Compounds/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Imidazoles/chemistry , Imidazoles/pharmacology , Molecular Structure , Pyrans/chemical synthesis , Pyrans/chemistry , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Viral Nonstructural Proteins/metabolism
13.
Front Plant Sci ; 7: 1413, 2016.
Article in English | MEDLINE | ID: mdl-27729915

ABSTRACT

The Mildew resistance Locus O (MLO) family is unique to plants, containing genes that were initially identified as a susceptibility factor to powdery mildew pathogens. However, little is known about the roles and functional diversity of this family in rice, a model crop plant. The rice genome has 12 potential MLO family members. To achieve systematic functional assignments, we performed a phylogenomic analysis by integrating meta-expression data obtained from public sources of microarray data and real-time expression data into a phylogenic tree. Subsequently, we identified 12 MLO genes with various tissue-preferred patterns, including leaf, root, pollen, and ubiquitous expression. This suggested their functional diversity for morphological agronomic traits. We also used these integrated transcriptome data within a phylogenetic context to estimate the functional redundancy or specificity among OsMLO family members. Here, OsMLO12 showed preferential expression in mature pollen; OsMLO4, in the root tips; OsMLO10, throughout the roots except at the tips; and OsMLO8, expression preferential to the leaves and trinucleate pollen. Of particular interest to us was the diurnal expression of OsMLO1, OsMLO3, and OsMLO8, which indicated that they are potentially significant in responses to environmental changes. In osdxr mutants that show defects in the light response, OsMLO1, OsMLO3, OsMLO8, and four calmodulin genes were down-regulated. This finding provides insight into the novel functions of MLO proteins associated with the light-responsive methylerythritol 4-phosphate pathway. In addition, abiotic stress meta-expression data and real-time expression analysis implied that four and five MLO genes in rice are associated with responses to heat and cold stress, respectively. Upregulation of OsMLO3 by Magnaporthe oryzae infection further suggested that this gene participates in the response to pathogens. Our analysis has produced fundamental information that will enhance future studies of the diverse developmental or physiological phenomena mediated by the MLO family in this model plant system.

14.
J Med Chem ; 57(5): 2013-32, 2014 Mar 13.
Article in English | MEDLINE | ID: mdl-24521299

ABSTRACT

The biphenyl derivatives 2 and 3 are prototypes of a novel class of NS5A replication complex inhibitors that demonstrate high inhibitory potency toward a panel of clinically relevant HCV strains encompassing genotypes 1-6. However, these compounds exhibit poor systemic exposure in rat pharmacokinetic studies after oral dosing. The structure-activity relationship investigations that improved the exposure properties of the parent bis-phenylimidazole chemotype, culminating in the identification of the highly potent NS5A replication complex inhibitor daclatasvir (33) are described. An element critical to success was the realization that the arylglycine cap of 2 could be replaced with an alkylglycine derivative and still maintain the high inhibitory potency of the series if accompanied with a stereoinversion, a finding that enabled a rapid optimization of exposure properties. Compound 33 had EC50 values of 50 and 9 pM toward genotype-1a and -1b replicons, respectively, and oral bioavailabilities of 38-108% in preclinical species. Compound 33 provided clinical proof-of-concept for the NS5A replication complex inhibitor class, and regulatory approval to market it with the NS3/4A protease inhibitor asunaprevir for the treatment of HCV genotype-1b infection has recently been sought in Japan.


Subject(s)
Antiviral Agents/pharmacology , Enzyme Inhibitors/pharmacology , Hepacivirus/drug effects , Imidazoles/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Virus Replication/drug effects , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Area Under Curve , Carbamates , Dogs , Drug Discovery , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Hepacivirus/enzymology , Hepacivirus/physiology , Imidazoles/chemistry , Imidazoles/pharmacokinetics , Magnetic Resonance Spectroscopy , Pyrrolidines , Rats , Spectrometry, Mass, Electrospray Ionization , Structure-Activity Relationship , Valine/analogs & derivatives
15.
J Med Chem ; 57(5): 1995-2012, 2014 Mar 13.
Article in English | MEDLINE | ID: mdl-24437689

ABSTRACT

A medicinal chemistry campaign that was conducted to address a potential genotoxic liability associated with an aniline-derived scaffold in a series of HCV NS5A inhibitors with dual GT-1a/-1b inhibitory activity is described. Anilides 3b and 3c were used as vehicles to explore structural modifications that retained antiviral potency while removing the potential for metabolism-based unmasking of the embedded aniline. This effort resulted in the discovery of a highly potent biarylimidazole chemotype that established a potency benchmark in replicon assays, particularly toward HCV GT-1a, a strain with significant clinical importance. Securing potent GT-1a activity in a chemotype class lacking overt structural liabilities was a critical milestone in the effort to realize the full clinical potential of targeting the HCV NS5A protein.


Subject(s)
Antiviral Agents/pharmacology , Genotype , Hepacivirus/drug effects , Imidazoles/pharmacology , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Replicon/drug effects , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Crystallography, X-Ray , Drug Discovery , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Hepacivirus/enzymology , Hepacivirus/genetics , Hepacivirus/physiology , Imidazoles/chemistry , Imidazoles/pharmacokinetics , Magnetic Resonance Spectroscopy , Spectrometry, Mass, Electrospray Ionization , Structure-Activity Relationship
16.
J Med Chem ; 57(5): 1976-94, 2014 Mar 13.
Article in English | MEDLINE | ID: mdl-23573957

ABSTRACT

A series of symmetrical E-stilbene prolinamides that originated from the library-synthesized lead 3 was studied with respect to HCV genotype 1a (G-1a) and genotype 1b (G-1b) replicon inhibition and selectivity against BVDV and cytotoxicity. SAR emerging from an examination of the prolinamide cap region revealed 11 to be a selective HCV NS5A inhibitor exhibiting submicromolar potency against both G-1a and G-1b replicons. Additional structural refinements resulted in the identification of 30 as a potent, dual G-1a/1b HCV NS5A inhibitor.


Subject(s)
Antiviral Agents/pharmacology , Genotype , Hepacivirus/drug effects , Protease Inhibitors/pharmacology , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Replicon/drug effects , Viral Nonstructural Proteins/antagonists & inhibitors , Virus Replication/drug effects , Antiviral Agents/chemistry , Hepacivirus/genetics , Hepacivirus/physiology , Magnetic Resonance Spectroscopy , Models, Molecular , Protease Inhibitors/chemistry , Spectrometry, Mass, Electrospray Ionization
17.
Virology ; 444(1-2): 343-54, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23896639

ABSTRACT

The hepatitis C virus NS5A protein is an established and clinically validated target for antiviral intervention by small molecules. Characterizations are presented of compounds identified as potent inhibitors of HCV replication to provide insight into structural elements that interact with the NS5A protein. UV-activated cross linking and affinity isolation was performed with one series to probe the physical interaction between the inhibitors and the NS5A protein expressed in HCV replicon cells. Resistance mapping with the second series was used to determine the functional impact of specific inhibitor subdomains on the interaction with NS5A. The data provide evidence for a direct high-affinity interaction between these inhibitors and the NS5A protein, with the interaction dependent on inhibitor stereochemistry. The functional data supports a model of inhibition that implicates inhibitor binding by covalently combining distinct pharmacophores across an NS5A dimer interface to achieve maximal inhibition of HCV replication.


Subject(s)
Antiviral Agents/pharmacology , Enzyme Inhibitors/pharmacology , Hepacivirus/drug effects , Hepacivirus/enzymology , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Viral Nonstructural Proteins/antagonists & inhibitors , Drug Resistance, Viral , Humans , Protein Binding
18.
Bioorg Med Chem Lett ; 23(15): 4428-35, 2013 Aug 01.
Article in English | MEDLINE | ID: mdl-23803586

ABSTRACT

The isoquinolinamide series of HCV NS5A inhibitors exemplified by compounds 2b and 2c provided the first dual genotype-1a/1b (GT-1a/1b) inhibitor class that demonstrated a significant improvement in potency toward GT-1a replicons compared to that of the initial program lead, stilbene 2a. Structure-activity relationship (SAR) studies that uncovered an alternate phenylglycine-based cap series that exhibit further improvements in virology profile, along with some insights into the pharmacophoric elements associated with the GT-1a potency, are described.


Subject(s)
Antiviral Agents/chemistry , Glycine/analogs & derivatives , Hepacivirus/enzymology , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacokinetics , Crystallography, X-Ray , Drug Evaluation, Preclinical , Genotype , Glycine/chemical synthesis , Glycine/chemistry , Glycine/pharmacokinetics , Half-Life , Hepacivirus/genetics , Hepacivirus/physiology , Microsomes, Liver/metabolism , Molecular Conformation , Rats , Structure-Activity Relationship , Viral Nonstructural Proteins/metabolism , Virus Replication/drug effects
19.
Bioorg Med Chem Lett ; 23(3): 779-84, 2013 Feb 01.
Article in English | MEDLINE | ID: mdl-23273521

ABSTRACT

In a recent disclosure, we described the discovery of dimeric, prolinamide-based NS5A replication complex inhibitors exhibiting excellent potency towards an HCV genotype 1b replicon. That disclosure dealt with the SAR exploration of the peripheral region of our lead chemotype, and herein is described the SAR uncovered from a complementary effort that focused on the central core region. From this effort, the contribution of the core region to the overall topology of the pharmacophore, primarily vector orientation and planarity, was determined, with a set of analogs exhibiting <10 nM EC(50) in a genotype 1b replicon assay.


Subject(s)
Antiviral Agents/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/pharmacology , Carbamates , Hepacivirus/drug effects , Imidazoles/chemistry , Imidazoles/pharmacology , Inhibitory Concentration 50 , Molecular Structure , Proline/analogs & derivatives , Proline/chemistry , Proline/pharmacology , Pyrrolidines , Structure-Activity Relationship , Valine/analogs & derivatives , Viral Nonstructural Proteins/chemistry , Virus Replication/drug effects
20.
Bioorg Med Chem Lett ; 22(19): 6063-6, 2012 Oct 01.
Article in English | MEDLINE | ID: mdl-22959243

ABSTRACT

In a previous disclosure,(1) we reported the dimerization of an iminothiazolidinone to form 1, a contributor to the observed inhibition of HCV genotype 1b replicon activity. The dimer was isolated via bioassay-guided fractionation experiments and shown to be a potent inhibitor of genotype 1b HCV replication for which resistance mapped to the NS5A protein. The elements responsible for governing HCV inhibitory activity were successfully captured in the structurally simplified stilbene prolinamide 2. We describe herein the early SAR and profiling associated with stilbene prolinamides that culminated in the identification of analogs with PK properties sufficient to warrant continued commitment to this chemotype. These studies represent the key initial steps toward the discovery of daclatasvir (BMS-790052), a compound that has demonstrated clinical proof-of-concept for inhibiting the NS5A replication complex in the treatment of HCV infection.


Subject(s)
Antiviral Agents/pharmacology , Imidazoles/pharmacology , Proline/analogs & derivatives , Stilbenes/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Virus Replication/drug effects , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Carbamates , Dose-Response Relationship, Drug , Imidazoles/chemical synthesis , Imidazoles/chemistry , Molecular Structure , Proline/chemical synthesis , Proline/chemistry , Proline/pharmacology , Pyrrolidines , Stilbenes/chemical synthesis , Stilbenes/chemistry , Structure-Activity Relationship , Valine/analogs & derivatives
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