Novel Glycoprotein VI Antagonists as Antithrombotics: Synthesis, Biological Evaluation, and Molecular Modeling Studies on 2,3-Disubstituted Tetrahydropyrido(3,4‑<i>b</i>)indoles

The development of small molecule inhibitors targeting GPVI has promising therapeutic role, as they inhibit arterial thrombosis with limited risk of bleeding. Among the compounds showing in vivo antithrombotic activity, the most active compound <b>6b</b> (ED₅₀ = 28.36 μmol/kg po in mice) showed improved inhibition for collagen (IC₅₀ = 6.7 μM), CRP-XL (IC₅₀ = 53.5 μM), and convulxin (CVX) (IC₅₀ = 5.7 μM) mediated platelet aggregation as compared to losartan (LOS) (collagen, IC₅₀ = 10.4 μM; CRP-XL, IC₅₀ = 158 μM; CVX, IC₅₀ = 11 μM) than any of its enantiomers <i>S</i> (<b>6c</b>) (collagen, IC₅₀ = 25.3 μM; CRP-XL, IC₅₀ = 181.4 μM; CVX, IC₅₀ = 9 μM) and <i>R</i> (<b>6d</b>) (collagen, IC₅₀ = 126.3 μM; CRP-XL, IC₅₀ > 500 μM; CVX, IC₅₀ = 86.8 μM). Compound <b>6b</b> also inhibited platelet P-selectin expression and thus may diminish atherosclerosis. The molecular interactions of both enantiomers <b>6c</b> and <b>6d</b> at the GPVI receptor have been explained through docking studies

Novel Glycoprotein VI Antagonists as Antithrombotics: Synthesis, Biological Evaluation, and Molecular Modeling Studies on 2,3-Disubstituted Tetrahydropyrido(3,4‑<i>b</i>)indoles

The development of small molecule inhibitors targeting GPVI has promising therapeutic role, as they inhibit arterial thrombosis with limited risk of bleeding. Among the compounds showing in vivo antithrombotic activity, the most active compound <b>6b</b> (ED₅₀ = 28.36 μmol/kg po in mice) showed improved inhibition for collagen (IC₅₀ = 6.7 μM), CRP-XL (IC₅₀ = 53.5 μM), and convulxin (CVX) (IC₅₀ = 5.7 μM) mediated platelet aggregation as compared to losartan (LOS) (collagen, IC₅₀ = 10.4 μM; CRP-XL, IC₅₀ = 158 μM; CVX, IC₅₀ = 11 μM) than any of its enantiomers <i>S</i> (<b>6c</b>) (collagen, IC₅₀ = 25.3 μM; CRP-XL, IC₅₀ = 181.4 μM; CVX, IC₅₀ = 9 μM) and <i>R</i> (<b>6d</b>) (collagen, IC₅₀ = 126.3 μM; CRP-XL, IC₅₀ > 500 μM; CVX, IC₅₀ = 86.8 μM). Compound <b>6b</b> also inhibited platelet P-selectin expression and thus may diminish atherosclerosis. The molecular interactions of both enantiomers <b>6c</b> and <b>6d</b> at the GPVI receptor have been explained through docking studies

Novel Glycoprotein VI Antagonists as Antithrombotics: Synthesis, Biological Evaluation, and Molecular Modeling Studies on 2,3-Disubstituted Tetrahydropyrido(3,4‑<i>b</i>)indoles

The development of small molecule inhibitors targeting GPVI has promising therapeutic role, as they inhibit arterial thrombosis with limited risk of bleeding. Among the compounds showing in vivo antithrombotic activity, the most active compound <b>6b</b> (ED₅₀ = 28.36 μmol/kg po in mice) showed improved inhibition for collagen (IC₅₀ = 6.7 μM), CRP-XL (IC₅₀ = 53.5 μM), and convulxin (CVX) (IC₅₀ = 5.7 μM) mediated platelet aggregation as compared to losartan (LOS) (collagen, IC₅₀ = 10.4 μM; CRP-XL, IC₅₀ = 158 μM; CVX, IC₅₀ = 11 μM) than any of its enantiomers <i>S</i> (<b>6c</b>) (collagen, IC₅₀ = 25.3 μM; CRP-XL, IC₅₀ = 181.4 μM; CVX, IC₅₀ = 9 μM) and <i>R</i> (<b>6d</b>) (collagen, IC₅₀ = 126.3 μM; CRP-XL, IC₅₀ > 500 μM; CVX, IC₅₀ = 86.8 μM). Compound <b>6b</b> also inhibited platelet P-selectin expression and thus may diminish atherosclerosis. The molecular interactions of both enantiomers <b>6c</b> and <b>6d</b> at the GPVI receptor have been explained through docking studies

Cohort profile: the German Diabetes Study (GDS)

BACKGROUND: The German Diabetes Study (GDS) is a prospective longitudinal cohort study describing the impact of subphenotypes on the course of the disease. GDS aims at identifying prognostic factors and mechanisms underlying the development of related comorbidities. STUDY DESIGN AND METHODS: The study comprises intensive phenotyping within 12 months after clinical diagnosis, at 5-year intervals for 20 years and annual telephone interviews in between. Dynamic tests, including glucagon, mixed meal, intravenous glucose tolerance and hyperinsulinemic clamp tests, serve to assess beta-cell function and tissue-specific insulin sensitivity. Magnetic resonance imaging and multinuclei spectroscopy allow quantifying whole-body fat distribution, tissue-specific lipid deposition and energy metabolism. Comprehensive analyses of microvascular (nerve, eye, kidney) and macrovascular (endothelial, cardiorespiratory) morphology and function enable identification and monitoring of comorbidities. The GDS biobank stores specimens from blood, stool, skeletal muscle, subcutaneous adipose tissue and skin for future analyses including multiomics, expression profiles and histology. Repeated questionnaires on socioeconomic conditions, patient-reported outcomes as quality of life, health-related behavior as physical activity and nutritional habits are a specific asset of GDS. This study will recruit 3000 patients and a group of humans without familiy history of diabetes. 237 type 1 and 456 type 2 diabetes patients have been already included

MOESM2 of Cohort profile: the German Diabetes Study (GDS)

Additional file 2. Risk analysis and risk mitigation measures