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1.
Int J Qual Stud Health Well-being ; 19(1): 2367844, 2024 Dec.
Article in English | MEDLINE | ID: mdl-38912882

ABSTRACT

BACKGROUND: Health agency refers to one's capacity to form health-related goals, experience control, and possess the means to pursue them. Low socioeconomic status (SES) is linked to impaired health agency and increased risk of adverse pregnancy outcomes, potentially due to a reduced tendency to seek care. Better healthcare availability may not improve their pregnancy outcomes, and therefore improved understanding of maternal health agency is paramount. METHODS: Semi-structured interviews were conducted with 15 participants who either had children or desired to have them. Low SES was determined by neighborhood median income and educational attainment. A thematic content analyses was conducted. RESULTS: Two themes emerged: 1) Origin and development of personal goals, and 2) Awareness and competence. Participant's goals stemmed from cultural norms, personal narratives, and intuition. Integrated goals were those participants valued highly, were aware of, and strived for. Four subthemes were identified in goal-awareness and competence. Internal conflict due to discrepancies between goals and behavior resulted in the need to balance the burdens and benefits of behavior change. CONCLUSION: Maternal health agency is a modifiable outcome dependent on goal-awareness and various factors. Impaired agency seemed to stem from lack of goal-awareness rather than an inability to meet established pillars.


Subject(s)
Goals , Maternal Health , Qualitative Research , Social Class , Humans , Female , Adult , Pregnancy , Young Adult , Poverty , Low Socioeconomic Status
2.
JMIR Hum Factors ; 11: e53614, 2024 Apr 22.
Article in English | MEDLINE | ID: mdl-38648092

ABSTRACT

BACKGROUND: A low socioeconomic status is associated with a vulnerable health status (VHS) through the accumulation of health-related risk factors, such as poor lifestyle behaviors (eg, inadequate nutrition, chronic stress, and impaired health literacy). For pregnant women, a VHS translates into a high incidence of adverse pregnancy outcomes and therefore pregnancy-related inequity. We hypothesize that stimulating adequate pregnancy preparation, targeting lifestyle behaviors and preconception care (PCC) uptake, can reduce these inequities and improve the pregnancy outcomes of women with a VHS. A nudge is a behavioral intervention aimed at making healthy choices easier and more attractive and may therefore be a feasible way to stimulate engagement in pregnancy preparation and PCC uptake, especially in women with a VHS. To support adequate pregnancy preparation, we designed a mobile health (mHealth) app, Pregnant Faster, that fits the preferences of women with a VHS and uses nudging to encourage PCC consultation visits and engagement in education on healthy lifestyle behaviors. OBJECTIVE: This study aimed to test the feasibility of Pregnant Faster by determining usability and user satisfaction, the number of visited PCC consultations, and the course of practical study conduction. METHODS: Women aged 18-45 years, with low-to-intermediate educational attainment, who were trying to become pregnant within 12 months were included in this open cohort. Recruitment took place through social media, health care professionals, and distribution of flyers and posters from September 2021 until June 2022. Participants used Pregnant Faster daily for 4 weeks, earning coins by reading blogs on pregnancy preparation, filling out a daily questionnaire on healthy lifestyle choices, and registering for a PCC consultation with a midwife. Earned coins could be spent on rewards, such as fruit, mascara, and baby products. Evaluation took place through the mHealth App Usability Questionnaire (MAUQ), an additional interview or questionnaire, and assessment of overall study conduction. RESULTS: Due to limited inclusions, the inclusion criterion "living in a deprived neighborhood" was dropped. This resulted in the inclusion of 47 women, of whom 39 (83%) completed the intervention. In total, 16 (41%) of 39 participants visited a PCC consultation, with their main motivation being obtaining personalized information. The majority of participants agreed with 16 (88.9%) of 18 statements of the MAUQ, indicating high user satisfaction. The mean rating was 7.7 (SD 1.0) out of 10. Points of improvement included recruitment of the target group, simplification of the log-in system, and automation of manual tasks. CONCLUSIONS: Nudging women through Pregnant Faster to stimulate pregnancy preparation and PCC uptake has proven feasible, but the inclusion criteria must be revised. A substantial number of PCC consultations were conducted, and this study will therefore be continued with an open cohort of 400 women, aiming to establish the (cost-)effectiveness of an updated version, named Pregnant Faster 2. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/45293.


Subject(s)
Mobile Applications , Preconception Care , Adolescent , Adult , Female , Humans , Middle Aged , Pregnancy , Young Adult , Feasibility Studies , Health Status , Pilot Projects , Preconception Care/methods , Vulnerable Populations
3.
JMIR Res Protoc ; 12: e45293, 2023 Aug 09.
Article in English | MEDLINE | ID: mdl-37556197

ABSTRACT

BACKGROUND: Women with a low socioeconomic status often have a vulnerable health status due to an accumulation of health-deteriorating factors such as poor lifestyle behaviors, including inadequate nutrition, mental stressors, and impaired health literacy and agency, which puts them at an unnecessary high risk of adverse pregnancy outcomes. Adequately preparing for pregnancy through preconception care (PCC) uptake and lifestyle improvement can improve these outcomes. We hypothesize that nudging is a successful way of encouraging engagement in PCC. A nudge is a behavioral intervention that changes choice behavior through influencing incentives. The mobile health (mHealth) app-based loyalty program Pregnant Faster aims to reward women in an ethically justified way and nudges to engage in pregnancy preparation by visiting a PCC consultation. OBJECTIVE: Here, we first describe the process of the cocreation of the mHealth app Pregnant Faster that aims to increase engagement in pregnancy preparation by women with a vulnerable health status. Second, we describe the cohort study design to assess the feasibility of Pregnant Faster. METHODS: The content of the app is based on the eHealth lifestyle coaching program Smarter Pregnancy, which has proven to be effective in ameliorating preconceptional lifestyle behaviors (folic acid, vegetables, fruits, smoking, and alcohol) and an interview study pertaining to the preferences of the target group with regard to an mHealth app stimulating PCC uptake. For moral guidance on the design, an ethical framework was developed based on the bioethical principles of Beauchamp and Childress. The app was further developed through iterative cocreation with the target group and health care providers. For 4 weeks, participants will engage with Pregnant Faster, during which opportunities will arise to earn coins such as reading informative blogs and registering for a PCC consultation. Coins can be spent on small fun rewards, such as folic acid, fruits, and mascara. Pregnant Faster's feasibility will be tested in a study including 40 women aged 18 to 45 years, who are preconceptional or <8 weeks pregnant, with a low educational level, and living in a deprived neighborhood. The latter 2 factors will serve as a proxy of a low socioeconomic status. Recruitment will take place through flyers, social media, and health care practices. After finalization, participants will evaluate the app through the "mHealth App Usability Questionnaire" and additional interviews or questionnaires. RESULTS: Results are expected to be published by December 2023. CONCLUSIONS: Pregnant Faster has been designed through iterative cocreation with the target group and health care professionals. With the designed study, we will test Pregnant Faster's feasibility. If overall user satisfaction and PCC uptake is achieved, the app will be further developed and the cohort will be continued with an additional 400 inclusions to establish effectiveness. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/45293.

4.
BMC Public Health ; 23(1): 43, 2023 01 06.
Article in English | MEDLINE | ID: mdl-36609315

ABSTRACT

BACKGROUND: Living in socially disadvantaged circumstances has a widespread impact on one's physical and mental health. That is why individuals living in this situation are often considered vulnerable. When pregnant, not only the woman's health is affected, but also that of her (unborn) child. It is well accepted that vulnerable populations experience worse (perinatal) health, however, little is known about the lived adversities and health of these vulnerable individuals. OBJECTIVES: With this article, insights into this group of highly vulnerable pregnant women are provided by describing the adversities these women face and their experienced well-being. METHODS: Highly vulnerable women were recruited when referred to tailored social care during pregnancy. Being highly vulnerable was defined as facing at least three different adversities divided over two or more life-domains. The heat map method was used to assess the interplay between adversities from the different life domains. Demographics and results from the baseline questionnaires on self-sufficiency and perceived health and well-being were presented. RESULTS: Nine hundred nineteen pregnant women were referred to social care (2016-2020). Overall, women had a median of six adversities, distributed over four life-domains. The heat map revealed a large variety in lived adversities, which originated from two parental clusters, one dominated by financial adversities and the other by a the combination of a broad range of adversities. The perceived health was moderate, and 25-34% experienced moderate to severe levels of depression, anxiety or stress. This did not differ between the two parental clusters. CONCLUSIONS: This study shows that highly vulnerable pregnant women deal with multiple adversities affecting not only their social and economic position but also their health and well-being.


Subject(s)
Mothers , Pregnant Women , Child , Female , Pregnancy , Humans , Pregnant Women/psychology , Anxiety/epidemiology , Parturition , Health Status
5.
BMC Pregnancy Childbirth ; 22(1): 559, 2022 Jul 13.
Article in English | MEDLINE | ID: mdl-35831786

ABSTRACT

BACKGROUND: Women with a vulnerable health status, as determined by a low socioeconomic status and poor lifestyle behaviours, are at risk for adverse pregnancy outcomes. Offering tailored preconception lifestyle care can significantly help to improve pregnancy outcomes. We hypothesize that so-called 'nudges' can be a successful way of increasing the uptake of preconception lifestyle care. A nudge is a behavioural intervention that supports healthy choices by making them easier to choose. Nudging, however, raises many moral questions. Effectiveness and respect for autonomy are, among other criteria, required for a nudge to be morally permissible. In general, the target group knows best what they find permissible and what would motivate them to change their lifestyle. Therefore, this study - conducted in women with a vulnerable health status - aimed to identify their preferences towards a nudge, provided via a mobile application that aims to help them adopt healthy lifestyle behaviours by offering rewards.  METHODS: We conducted semi-structured interviews with twelve women with a vulnerable health status. A framework approach was used to analyse the data. A thematic content analysis was conducted on five themes: (1) "Usefulness of an app as an integral information source", (2) "Permissibility and effects of offering rewards", (3) "Preferences regarding content", (4) "Preferences regarding type of rewards and system of allocation", and (5) "Barriers". RESULTS: Of the 12 participants, 11 deemed an app as integral information source concerning the preconception period useful. None of the participants objected to being nudged i.e., being rewarded for healthy behaviour. All participants stated that they would like the app to contain information on healthy nutrition and 8 participants wanted to know how to get pregnant quickly. Furthermore, participants stated that the freedom to choose the timing and content of the reward would increase the probability of successful behavioural change, and having to pay or contact a healthcare provider to access the app may prevent women using the app. CONCLUSIONS: These insights into the preferences of women with a vulnerable health status towards nudging will inform the design of an effective app-based nudge. This may help to improve prepregnancy health as investment in health of current and future generations.


Subject(s)
Healthy Lifestyle , Preconception Care , Female , Health Status , Humans , Preconception Care/methods , Pregnancy , Qualitative Research , Social Responsibility
6.
Patient Educ Couns ; 105(7): 1743-1760, 2022 07.
Article in English | MEDLINE | ID: mdl-34872804

ABSTRACT

OBJECTIVES: To explore, based on the existing body of literature, main characteristics of prenatal counseling for parents at risk for extreme preterm birth. METHODS: A scoping review was conducted searching Embase, Medline, Web of Science, Cochrane, CINAHL, and Google Scholar. RESULTS: 46 articles were included. 27 of them were published between 2017 and 2021. More than half of them were conducted in the United States of America. Many different study designs were represented. The following characteristics were identified: personalization, parent-physician relationships, shared decision-making, physician bias, emotions, anxiety, psychosocial factors, parental values, religion, spirituality, hope, quality of life, and uncertainty. CONCLUSIONS: Parental values are mentioned in 37 of the included articles. Besides this, uncertainty, shared decision-making, and emotions are most frequently mentioned in the literature. However, reflecting on the interrelation between all characteristics leads us to conclude that personalization is the most notable trend in prenatal counseling practices. More and more, it is valued to adjust the counseling to the parent(s). PRACTICE IMPLICATIONS: This scoping review emphasizes again the complexity of prenatal counseling at the limit of viability. It offers an exploration of how it is currently approached, and reflects on how future research can contribute to optimizing it.


Subject(s)
Premature Birth , Counseling , Decision Making , Female , Humans , Infant, Newborn , Parents/psychology , Pregnancy , Quality of Life , Uncertainty
8.
J Med Ethics ; 2022 Dec 08.
Article in English | MEDLINE | ID: mdl-36600611

ABSTRACT

Formulating sound and acceptable embryo research policy remains challenging especially in a pluralistic world. This challenge has acquired a new dimension of complexity with the advent of so-called embryo models, which are derived from stem cells. In this article, we present a normative strategy to facilitate the process of sound policy-making in the field of human embryology. This strategy involves seeking neutral agreements on higher level theories and doctrines as well as seeking agreements on the level of concrete policy proposals. We call this strategy: going high and low. By going high and low, the plurality of reasonable moral and epistemic convictions of stakeholders involved in the domain of human embryology is respected while the process of policy-making in this area is improved.

9.
Public Health Ethics ; 14(2): 168-179, 2021 Jul.
Article in English | MEDLINE | ID: mdl-34650620

ABSTRACT

Poor pregnancy outcomes and inequalities in these outcomes remain a major challenge, even in prosperous societies that have high-quality health care and public health policy in place. In this article, we propose that justice demands the improvement of what we call the 'health agency' of parents-to-be as part of a response to these poor outcomes. We take health agency to have three aspects: (i) the capacity to form health-goals one has reason to value, (ii) the control one perceives to have over achieving those health-goals and (iii) the freedom(s) one has to achieve those health-goals. We will moreover argue that this demand of justice can be best based on a perfectionist rather than neutralist method of justification. Subsequently, we will argue that perfectionist policy may be paternalistic but not wrongfully paternalistic. This leads us to conclude that perfectionism should be adopted to inform and justify public health policy that is aimed at improving health agency in general and counteracting poor pregnancy outcomes and inequalities in perinatal health outcomes in particular.

10.
Am J Bioeth ; 21(9): 31-42, 2021 Sep.
Article in English | MEDLINE | ID: mdl-33871324

ABSTRACT

The aim of this article is twofold. First is to demonstrate that most values that underpin public health policy are a source of reasonable disagreement amongst citizens to whom said policy applies. This demands from the state to be explicit about whether it espouses neutrality or perfectionism to justify public health policy. Second is to argue in favor of a perfectionist mode of justification of public health policy. To do so I will argue that the lowest common denominator approach to public health policy justification to which neutralists are committed yields policy that is strong in justification but feeble in impact. Perfectionist public health policy does not face this problem. Perfectionism however, is allegedly elitist and objectionably paternalistic. I will argue that the former objection is based on an uncharitable reading of perfectionism. To mitigate the latter concern, I will offer a liberal proviso.


Subject(s)
Perfectionism , Dissent and Disputes , Humans , Paternalism , Public Health , Public Policy
11.
Front Pediatr ; 9: 634290, 2021.
Article in English | MEDLINE | ID: mdl-33598441

ABSTRACT

The current Dutch guideline on care at the edge of perinatal viability advises to consider initiation of active care to infants born from 24 weeks of gestational age on. This, only after extensive counseling of and shared decision-making with the parents of the yet unborn infant. Compared to most other European guidelines on this matter, the Dutch guideline may be thought to stand out for its relatively high age threshold of initiating active care, its gray zone spanning weeks 24 and 25 in which active management is determined by parental discretion, and a slight reluctance to provide active care in case of extreme prematurity. In this article, we explore the Dutch position more thoroughly. First, we briefly look at the previous and current Dutch guidelines. Second, we position them within the Dutch socio-cultural context. We focus on the Dutch prioritization of individual freedom, the abortion law and the perinatal threshold of viability, and a culturally embedded aversion of suffering. Lastly, we explore two possible adaptations of the Dutch guideline; i.e., to only lower the age threshold to consider the initiation of active care, or to change the type of guideline.

13.
Nicotine Tob Res ; 22(9): 1553-1559, 2020 08 24.
Article in English | MEDLINE | ID: mdl-31848622

ABSTRACT

INTRODUCTION: Smoking during pregnancy increases the risk of morbidity and mortality of the mother and child. The inability of the unborn child to protect itself, raises the social and academic responsibility to protect the child from the harmful effects of smoking. Interventions including rewards (incentives) for lifestyle changes are an upcoming trend and can encourage women to quit smoking. However, these incentives can, as we will argue, also have negative consequences, for example the restriction of personal autonomy and encouragement of smoking to become eligible for participation. To prevent these negative consequences, we developed an ethical framework that enables to assess and address unwanted consequences of incentive-based interventions whereby moral permissibility can be evaluated. AIMS AND METHODS: The possible adverse consequences of incentives were identified through an extensive literature search. Subsequently, we developed ethical criteria to identify these consequences based on the biomedical ethical principles of Beauchamp and Childress. RESULTS: Our framework consists of 12 criteria. These criteria concern (1) effectiveness, (2) support of a healthy lifestyle, (3) motivational for the target population, (4) stimulating unhealthy behavior, (5) negative attitudes, (6) personal autonomy, (7) intrinsic motivation, (8) privacy, (9) fairness, (10) allocation of incentives, (11) cost-effectiveness, and (12) health inequity. Based on these criteria, the moral permissibility of potential interventions can be evaluated. CONCLUSIONS: Incentives for smoking cessation are a response to the responsibility to protect the unborn child. But these interventions might have possible adverse effects. This ethical framework aims to identify and address ethical pitfalls in order to avoid these adverse effects. IMPLICATIONS: Although various interventions to promote smoking cessation during pregnancy exist, many women still smoke during pregnancy. Interventions using incentives for smoking cessation during pregnancy are a promising and upcoming trend but can have unwanted consequences. This ethical framework helps to identify and address ethical pitfalls in order to avoid these adverse effects.It can be a practical tool in the development and evaluation of these interventions and in evaluating the moral permissibility of interventions using incentives for smoking cessation during pregnancy.


Subject(s)
Health Promotion/ethics , Mothers/psychology , Motivation , Smoking Cessation/methods , Smoking Cessation/psychology , Smoking/therapy , Adult , Female , Humans , Pregnancy , Reward , Smoking/psychology
14.
J Med Vasc ; 44(5): 336-339, 2019 Sep.
Article in French | MEDLINE | ID: mdl-31474344

ABSTRACT

Jejunal pseudoaneurysm is a rare complication of pancreatitis, usually manifested by digestive bleeding when it ruptures into the digestive lumen. This complication is extremely rare and may be life-threatening. The diagnosis is based on abdominal angiographic computed tomography. Radiology allows therapeutic management through arterial embolization. This case report describes a pseudoaneurysm of jejunal artery that developed as the result of pancreatitis: A 77-year-old man seen in early September 2015 at the emergency department for acute pancreatitis had a pseudocyst infected and spontaneously fistulized into the jejunum lumen. His condition responded initially to symptomatic therapy, and he was discharged. He returned two years later, with digestive bleeding from jejunal pseudoaneurysm that had ruptured into the jejunal lumen. Angiographic embolization was performed as first-line treatment with good outcome. Bleeding more than two years after acute pancreatitis due to rupture of a jejunal pseudoaneurysm is an exceptional complication. Here we report a rare case of digestive hemorrhage caused by jejunal pseudoaneurysm, complicating acute pancreatitis.


Subject(s)
Aneurysm, False/etiology , Aneurysm, Ruptured/etiology , Arteries , Jejunum/blood supply , Pancreatitis/complications , Aged , Aneurysm, False/diagnostic imaging , Aneurysm, False/therapy , Aneurysm, Ruptured/diagnostic imaging , Aneurysm, Ruptured/therapy , Arteries/diagnostic imaging , Embolization, Therapeutic , Gastrointestinal Hemorrhage/etiology , Humans , Male , Pancreatitis/diagnosis , Treatment Outcome
15.
J Med Ethics ; 2018 Sep 04.
Article in English | MEDLINE | ID: mdl-30181162

ABSTRACT

Is it morally justifiable to force non-consenting pregnant women to submit to caesarean surgery to save their fetus in distress? Even though proponents and opponents largely agree on the interests at stake, such as the health and life of the fetus and the respect for bodily integrity and autonomy of pregnant women, they disagree on which moral weight to attach to these interests. This is why disagreements about the justifiability of forced caesareans tend to be pervasive and intractable. To sidestep this deadlock, we will focus on conditions that give rise to the 'caesarean dilemma' in the first place, namely the conflict between inherent norms and values medical professionals are committed to by virtue of being a medical professional. Using the reflective equilibrium, we will test the opponents' and proponents' considered judgments about forced caesareans against the norms and values they-as medical professionals-are committed to and determine whether they are coherent. Subsequently we will identify the proponents' incoherencies between the considered judgments and norms and values they are committed to and conclude that as long as these incoherencies are in place, forced caesareans are morally impermissible.

16.
J Dev Orig Health Dis ; 9(1): 58-62, 2018 02.
Article in English | MEDLINE | ID: mdl-28829006

ABSTRACT

Insights from the Developmental Origins of Health and Disease paradigm and epigenetics are elucidating the biological pathways through which social and environmental signals affect human health. These insights prompt a serious debate about how the structure of society affects health and what the responsibility of society is to counteract health inequalities. Unfortunately, oversimplified interpretations of insights from Developmental Origins of Health and Disease and epigenetics may be (mis)used to focus on the importance of individual responsibility for health rather than the social responsibility for health. In order to advance the debate on responsibility for health, we present an ethical framework to determine the social responsibility to counteract health inequalities. This is particularly important in a time where individual responsibility often justifies a passive response from policymakers.


Subject(s)
Global Health/ethics , Health Promotion/organization & administration , Healthcare Disparities/ethics , Prenatal Exposure Delayed Effects/prevention & control , Social Responsibility , Epigenesis, Genetic , Female , Health Promotion/methods , Healthy Lifestyle/ethics , Humans , Pregnancy , Prenatal Exposure Delayed Effects/ethnology , Prenatal Exposure Delayed Effects/genetics
17.
J Med Ethics ; 43(10): 702-706, 2017 10.
Article in English | MEDLINE | ID: mdl-28122991

ABSTRACT

There is an increasing interest in the possibility of using nudges to promote people's health. Following the advances in developmental biology and epigenetics, it is clear that one's health is not always the result of one's own choices. In the period surrounding pregnancy, maternal choice behaviour has a significant influence on perinatal morbidity and mortality as well as the development of chronic diseases later in life. One's health is thus a matter of one's own as well as one's maternal choices. Therefore, self-regarding and other-regarding nudges should be considered as viable strategies to promote health. In this article, we introduce the concept of other-regarding nudges. We use the harm principle and the principle of beneficence to justify these other-regarding nudges. We conclude by stressing the importance of a fair assessment of expectations towards the nudgee, when determining whether a nudge is aimed at preventing harm or promoting a good.


Subject(s)
Choice Behavior/ethics , Health Promotion , Pregnant Women , Public Health/ethics , Decision Making/ethics , Female , Health Behavior/ethics , Health Promotion/ethics , Humans , Persuasive Communication , Pregnancy , Risk Reduction Behavior
18.
J Med Chem ; 58(9): 3806-16, 2015 May 14.
Article in English | MEDLINE | ID: mdl-25844760

ABSTRACT

The medicinal chemistry community has directed considerable efforts toward the discovery of selective inhibitors of interleukin-2 inducible T-cell kinase (ITK), given its role in T-cell signaling downstream of the T-cell receptor (TCR) and the implications of this target for inflammatory disorders such as asthma. We have previously disclosed a structure- and property-guided lead optimization effort which resulted in the discovery of a new series of tetrahydroindazole-containing selective ITK inhibitors. Herein we disclose further optimization of this series that resulted in further potency improvements, reduced off-target receptor binding liabilities, and reduced cytotoxicity. Specifically, we have identified a correlation between the basicity of solubilizing elements in the ITK inhibitors and off-target antiproliferative effects, which was exploited to reduce cytotoxicity while maintaining kinase selectivity. Optimized analogues were shown to reduce IL-2 and IL-13 production in vivo following oral or intraperitoneal dosing in mice.


Subject(s)
Indazoles/chemistry , Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Cell Proliferation/drug effects , Crystallography, X-Ray , Cytotoxins/chemistry , Cytotoxins/pharmacology , Cytotoxins/toxicity , Female , Humans , Indazoles/pharmacology , Indazoles/toxicity , Interleukin-13/biosynthesis , Interleukin-2/biosynthesis , Jurkat Cells , Mice, Inbred C57BL , Models, Molecular , Molecular Structure , Phosphorylation , Receptors, Antigen, T-Cell/metabolism , Stereoisomerism , Structure-Activity Relationship , Sulfones/chemistry , Sulfones/pharmacology , Sulfones/toxicity , Sulfoxides/chemistry , Sulfoxides/pharmacology , Sulfoxides/toxicity
19.
Bioorg Med Chem Lett ; 24(24): 5818-5823, 2014 Dec 15.
Article in English | MEDLINE | ID: mdl-25455497

ABSTRACT

Starting from benzylpyrimidine 2, molecular modeling and X-ray crystallography were used to design highly potent inhibitors of Interleukin-2 inducible T-cell kinase (ITK). Sulfonylpyridine 4i showed sub-nanomolar affinity against ITK, was selective versus Lck and its activity in the Jurkat cell-based assay was greatly improved over 2.


Subject(s)
Drug Design , Protein Kinase Inhibitors/chemical synthesis , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyridines/chemistry , Binding Sites , Crystallography, X-Ray , Kinetics , Molecular Dynamics Simulation , Protein Binding , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Protein Structure, Tertiary , Protein-Tyrosine Kinases/metabolism , Pyrazoles/chemistry , Pyridines/chemical synthesis , Pyridines/metabolism , Structure-Activity Relationship , Sulfones/chemistry
20.
J Med Chem ; 57(13): 5714-27, 2014 Jul 10.
Article in English | MEDLINE | ID: mdl-24918870

ABSTRACT

Interleukin-2 inducible T-cell kinase (ITK), a member of the Tec family of tyrosine kinases, plays a major role in T-cell signaling downstream of the T-cell receptor (TCR), and considerable efforts have been directed toward discovery of ITK-selective inhibitors as potential treatments of inflammatory disorders such as asthma. Using a previously disclosed indazole series of inhibitors as a starting point, and using X-ray crystallography and solubility forecast index (SFI) as guides, we evolved a series of tetrahydroindazole inhibitors with improved potency, selectivity, and pharmaceutical properties. Highlights include identification of a selectivity pocket above the ligand plane, and identification of appropriate lipophilic substituents to occupy this space. This effort culminated in identification of a potent and selective ITK inhibitor (GNE-9822) with good ADME properties in preclinical species.


Subject(s)
Indazoles/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Crystallography, X-Ray , Dogs , Drug Design , Humans , Indazoles/pharmacokinetics , Indazoles/pharmacology , Jurkat Cells , Kinetics , Mice , Models, Molecular , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Rats , Solubility , Structure-Activity Relationship
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