9 research outputs found
Discovery of 9-Cyclopropylethynyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one (GLPG1205), a unique GPR84 negative allosteric modulator undergoing evaluation in a phase II clinical trial
GPR84 is a medium chain free fatty acid-binding G-protein-coupled receptor associated with inflammatory and fibrotic diseases. As the only reported antagonist of GPR84 (PBI-4050) that displays relatively low potency and selectivity, a clear need exists for an improved modulator. Structural optimization of GPR84 antagonist hit 1, identified through high-throughput screening, led to the identification of potent and selective GPR84 inhibitor GLPG1205 (36). Compared with the initial hit, 36 showed improved potency in a guanosine 5′-O-[γ-thio]triphosphate assay, exhibited metabolic stability, and lacked activity against phosphodiesterase-4. This novel pharmacological tool allowed investigation of the therapeutic potential of GPR84 inhibition. At once-daily doses of 3 and 10 mg/kg, GLPG1205 reduced disease activity index score and neutrophil infiltration in a mouse dextran sodium sulfate-induced chronic inflammatory bowel disease model, with efficacy similar to positive-control compound sulfasalazine. The drug discovery steps leading to GLPG1205 identification, currently under phase II clinical investigation, are described herein
"Learning a way of thinking" - World Café on clinical reasoning in nursing and midwifery education and practice across five European Union countries
Clinical reasoning is a key attribute of nursing and midwifery professionals. As a part of the Erasmus plus project, we designed a study with the aim of exploring the understanding of clinical reasoning as a concept, experiences of teaching clinical reasoning and practices related to using clinical reasoning in nursing and midwifery. A qualitative study was carried out using the World Café method, involving 44 participants from five European countries. The participants represented diverse professional backgrounds, including nurses, midwives and lecturers. Our analytical approach was based on a thematic analysis. We categorized the data into three main categories, namely, “Spiral of thinking”, “The learning and teaching of a way of thinking” and “Clinical reasoning in real life”, all under an overarching theme, “Learning a way of thinking”. This study highlighted areas of learning and teaching which can be improved in current nursing and midwifery education. Furthermore, it identified barriers, facilitators and practices from five European countries which can be used in the further development of nursing and midwifery curricula and courses with the aim of enhancing clinical reasoning competence and ultimately improving patient care
Correction to Discovery, Structure–Activity Relationship, and Binding Mode of an Imidazo[1,2- a
Quality of dying and quality of end-of-life care of nursing home residents in six countries: An epidemiological study
Discovery of 2‑[[2-Ethyl-6-[4-[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]piperazin-1-yl]-8-methylimidazo[1,2‑<i>a</i>]pyridin-3-yl]methylamino]-4-(4-fluorophenyl)thiazole-5-carbonitrile (GLPG1690), a First-in-Class Autotaxin Inhibitor Undergoing Clinical Evaluation for the Treatment of Idiopathic Pulmonary Fibrosis
Autotaxin is a circulating
enzyme with a major role in the production
of lysophosphatic acid (LPA) species in blood. A role for the autotaxin/LPA
axis has been suggested in many disease areas including pulmonary
fibrosis. Structural modifications of the known autotaxin inhibitor
lead compound <b>1</b>, to attenuate hERG inhibition, remove
CYP3A4 time-dependent inhibition, and improve pharmacokinetic properties,
led to the identification of clinical candidate GLPG1690 (<b>11</b>). Compound <b>11</b> was able to cause a sustained reduction
of LPA levels in plasma in vivo and was shown
to be efficacious in a bleomycin-induced pulmonary fibrosis model
in mice and in reducing extracellular matrix deposition in the lung
while also reducing LPA 18:2 content in bronchoalveolar lavage fluid.
Compound <b>11</b> is currently being evaluated in an exploratory
phase 2a study in idiopathic pulmonary fibrosis patients
Discovery of 2‑[[2-Ethyl-6-[4-[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]piperazin-1-yl]-8-methylimidazo[1,2‑<i>a</i>]pyridin-3-yl]methylamino]-4-(4-fluorophenyl)thiazole-5-carbonitrile (GLPG1690), a First-in-Class Autotaxin Inhibitor Undergoing Clinical Evaluation for the Treatment of Idiopathic Pulmonary Fibrosis
Autotaxin is a circulating
enzyme with a major role in the production
of lysophosphatic acid (LPA) species in blood. A role for the autotaxin/LPA
axis has been suggested in many disease areas including pulmonary
fibrosis. Structural modifications of the known autotaxin inhibitor
lead compound <b>1</b>, to attenuate hERG inhibition, remove
CYP3A4 time-dependent inhibition, and improve pharmacokinetic properties,
led to the identification of clinical candidate GLPG1690 (<b>11</b>). Compound <b>11</b> was able to cause a sustained reduction
of LPA levels in plasma in vivo and was shown
to be efficacious in a bleomycin-induced pulmonary fibrosis model
in mice and in reducing extracellular matrix deposition in the lung
while also reducing LPA 18:2 content in bronchoalveolar lavage fluid.
Compound <b>11</b> is currently being evaluated in an exploratory
phase 2a study in idiopathic pulmonary fibrosis patients
Discovery, Structure–Activity Relationship, and Binding Mode of an Imidazo[1,2‑<i>a</i>]pyridine Series of Autotaxin Inhibitors
Autotaxin
(ATX) is a secreted enzyme playing a major role in the
production of lysophosphatidic acid (LPA) in blood through hydrolysis
of lysophosphatidyl choline (LPC). The ATX–LPA signaling axis
arouses a high interest in the drug discovery industry as it has been
implicated in several diseases including cancer, fibrotic diseases,
and inflammation, among others. An imidazo[1,2-<i>a</i>]pyridine
series of ATX inhibitors was identified out of a high-throughput screening
(HTS). A cocrystal structure with one of these compounds and ATX revealed
a novel binding mode with occupancy of the hydrophobic pocket and
channel of ATX but no interaction with zinc ions of the catalytic
site. Exploration of the structure–activity relationship led
to compounds displaying high activity in biochemical and plasma assays,
exemplified by compound <b>40</b>. Compound <b>40</b> was
also able to decrease the plasma LPA levels upon oral administration
to rats