A novel series of benzo
acarbazole-based small molecule agonists of the thrombopoietin (Tpo) receptor is reported. Members of this series have been identified which are full agonists with functional ...potency <50
nM and oral bioavailability in mice.
A novel series of benzo
acarbazole-based small molecule agonists of the thrombopoietin (Tpo) receptor is reported. Starting from a 3.4
μM high throughput screen hit, members of this series have been identified which are full agonists with functional potency <50
nM and oral bioavailability in mice.
•We carried out vegetation studies in the ancient oak forest Hasbruch in Germany.•We analysed drivers of changes in vascular plant species richness.•We analysed the effect of management and ...vegetation type on these changes.•The main drivers for changes in species richness were light and water availability.•Effects of the drivers strongly depended on the vegetation type.
We carried out vegetation studies in the ancient Hasbruch forest, which provided the unique conditions of unmanaged (UM) and managed (M) stands in two vegetation types Stellario-Carpinetum loniceretosum (POOR) and stachyetosum (RICH) stands in one closed forest allowing us to study (1) the changes in species composition and richness over 20 years considering the entire forest as well as (2) group-specific changes.
Hasbruch forest in the lowlands of Lower Saxony, Germany.
In 2016 we resurveyed the vascular plant species composition of 79 semi-permanent plots analysed in 1996. General and group-specific trends as well as drivers of changes were analysed using DCA, PCA, LM, t-test, U test, ANOVA.
Tree and shrub layer coverage increased significantly in the entire forest. Herb layer species richness decreased significantly only in group RICH_UM. While the pH-value increased significantly in group POOR, it decreased significantly in group B. EIV F increased significantly in group POOR_M and decreased significantly in group RICH_UM. EIV L increased significantly in both of the managed groups, while it decreased significantly in group RICH_UM. An increase was found for EIV N in group POOR_M, whereas a decrease was found in group RICH_M. Strongly increasing species were Ilex aquifolium, Rubus fruticosus agg. and Hedera helix; strongly decreasing species Geum urbanum and Primula elatior. The change in species richness was positively affected by ΔpH and negatively affected by ΔT1cov in the entire forest.
The main drivers for changes in species richness and composition in the Hasbruch forest were light and water availability. The effects of the drivers strongly depended on the vegetation type. Changes in species composition were more pronounced in nutrient-rich forests than on nutrient-poor sites. In nutrient-rich forests, decreased groundwater influence led to decreased soil pH which especially affected typical woodland plants in a negative way. Management positively affected light-demanding species as well as some N-demanding species. Thus, unmanaged, nutrient-rich stands displayed the highest losses in species diversity. In the nutrient-poor stands, changes in species composition were not significantly related to changes in soil and management. However, increasing pH as well as increased Ellenberg L, F, and N values suggest a tendency towards eutrophication. This is possibly a consequence of N deposition and recovery from soil acidification.
Mutations in MEK1/2 have been described as a resistance mechanism to BRAF/MEK inhibitor treatment. We report the discovery of a novel ATP-competitive MEK1/2 inhibitor with efficacy in wildtype (WT) ...and mutant MEK12 models. Starting from a HTS hit, we obtained selective, cellularly active compounds that showed equipotent inhibition of WT MEK1/2 and a panel of MEK1/2 mutant cell lines. Using a structure-based approach, the optimization addressed the liabilities by systematic analysis of molecular matched pairs (MMPs) and ligand conformation. Addition of only three heavy atoms to early tool compound 6 removed Cyp3A4 liabilities and increased the cellular potency by 100-fold, while reducing log P by 5 units. Profiling of MAP855, compound 30, in pharmacokinetic–pharmacodynamic and efficacy studies in BRAF-mutant models showed comparable efficacy to clinical MEK1/2 inhibitors. Compound 30 is a novel highly potent and selective MEK1/2 kinase inhibitor with equipotent inhibition of WT and mutant MEK1/2, whose drug-like properties allow further investigation in the mutant MEK setting upon BRAF/MEK therapy.
The discovery, synthesis, and optimization of compound 1 from a high-throughput screening hit to highly potent and selective peroxisome proliferator-activated receptor δ (PPARδ) agonists are ...reported. The synthesis and structure−activity relationship in this series are described in detail. On the basis of a general schematic PPAR pharmacophore model, scaffold 1 was divided into headgroup, linker, and tailgroup and successively optimized for PPAR activation using in vitro PPAR transactivation assays. A (2-methylphenoxy)acetic acid headgroup, a flexible linker, and a five-membered heteroaromatic center ring with two hydrophobic aryl substituents were required for efficient and selective PPARδ activation. The fine-tuning of these aryl substituents led to an array of highly potent and selective compounds such as compound 38c, displaying an excellent pharmacokinetic profile in mouse. In an in vivo acute dosing model, selected members of this array were shown to induce the expression of pyruvate dehydrogenase kinase-4 (PDK4) and uncoupling protein-3 (UCP3), genes that are known to be involved in energy homeostasis and regulated by PPARδ in skeletal muscle.
A series of highly potent and selective PPAR agonists is reported.
A series of highly potent and selective PPARδ agonists is described using the known non-selective ligand GW2433 as a structural ...template. Compound
1 is bioavailable, potent (10
nM), and shows no cross-activity with other PPAR subtypes up to 10
μM, making it a useful tool in studying the biological effects of selective PPARδ activation.
A structurally novel series of selective PPARδ agonists is reported.
We report the identification of a novel series of trisubstituted isoxazoles as PPAR activators from a high-throughput screen. A ...series of structural optimizations led to improved efficacy and excellent functional receptor selectivity for PPARδ. The isoxazoles represent a series of agonists which display a scaffold that lies outside the typical PPAR agonist motif.
The optimization of an isoxazole series to the potent, selective, and bioavailable PPARδ agonist LCI765 is reported. A co-crystal structure and in vivo properties of LCI765 are discussed.
A series of ...PPARδ-selective agonists was investigated and optimized for a favorable in vivo pharmacokinetic profile. Isoxazole
LCI765 (
17d) was found to be a potent and selective PPARδ agonist with good in vivo PK properties in mouse (
C
max
=
5.1
μM,
t
1/2
=
3.1
h).
LCI765 regulated expression of genes involved in energy homeostasis in relevant tissues when dosed orally in C57BL6 mice. A co-crystal structure of compound
LCI765 and the LBD of PPARδ is discussed.
The lead optimization of a novel series of benzo
acarbazole-based small molecule agonists of the thrombopoietin (Tpo) receptor is reported. Analog
21 demonstrates equivalent efficacy in the human ...megakaryocyte differentiation (CFU-mega) assay compared to Eltrombopag™.
The lead optimization of a novel series of benzo
acarbazole-based small molecule agonists of the thrombopoietin (Tpo) receptor is reported. The chemical instability of the dihydro-benzo
acarbazole lead
2 was successfully addressed in the design and evaluation of compounds which also demonstrated improved potency compared to
2. Members of the scaffold have been identified which are full agonists that demonstrate cellular functional potency <50
nM. Analog
21 demonstrates equivalent efficacy in the human megakaryocyte differentiation (CFU-mega) assay compared to Eltrombopag™.
A series of highly potent and selective PPARdelta agonists is described using the known non-selective ligand GW2433 as a structural template. Compound 1 is bioavailable, potent (10 nM), and shows no ...cross-activity with other PPAR subtypes up to 10 microM, making it a useful tool in studying the biological effects of selective PPARdelta activation.
We report the identification of a novel series of trisubstituted isoxazoles as PPAR activators from a high-throughput screen. A series of structural optimizations led to improved efficacy and ...excellent functional receptor selectivity for PPARdelta. The isoxazoles represent a series of agonists which display a scaffold that lies outside the typical PPAR agonist motif.
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