6 research outputs found
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New Associations between Drug-Induced Adverse Events in Animal Models and Humans Reveal Novel Candidate Safety Targets.
To improve our ability to extrapolate preclinical toxicity to humans, there is a need to understand and quantify the concordance of adverse events (AEs) between animal models and clinical studies. In the present work, we discovered 3011 statistically significant associations between preclinical and clinical AEs caused by drugs reported in the PharmaPendium database of which 2952 were new associations between toxicities encoded by different Medical Dictionary for Regulatory Activities terms across species. To find plausible and testable candidate off-target drug activities for the derived associations, we investigated the genetic overlap between the genes linked to both a preclinical and a clinical AE and the protein targets found to interact with one or more drugs causing both AEs. We discuss three associations from the analysis in more detail for which novel candidate off-target drug activities could be identified, namely, the association of preclinical mutagenicity readouts with clinical teratospermia and ovarian failure, the association of preclinical reflexes abnormal with clinical poor-quality sleep, and the association of preclinical psychomotor hyperactivity with clinical drug withdrawal syndrome. Our analysis successfully identified a total of 77% of known safety targets currently tested in in vitro screening panels plus an additional 431 genes which were proposed for investigation as future safety targets for different clinical toxicities. This work provides new translational toxicity relationships beyond AE term-matching, the results of which can be used for risk profiling of future new chemical entities for clinical studies and for the development of future in vitro safety panels.This work was supported as part of the PhD project of K.A.G funded by the European Research Council and AstraZeneca Early Oncology TD
Ligand-independent activity of the ghrelin receptor modulates AMPA receptor trafficking and supports memory formation
The biological signals of hunger, satiety, and memory are interconnected. The role of the hormone ghrelin in regulating feeding and memory makes ghrelin receptors attractive targets for associated disorders. We investigated
the effects of the high ligand-independent activity of the ghrelin receptor GHS-R1a on the physiology of excitatory
synapses in the hippocampus. Blocking this activity produced a decrease in the synaptic content of AMPA receptors in hippocampal neurons and a reduction in GluA1 phosphorylation at Ser845. Reducing the ligand-independent
activity of GHS-R1a increased the surface diffusion of AMPA receptors and impaired AMPA receptor–dependent
synaptic delivery induced by chemical long-term potentiation. Accordingly, we found that blocking this GHS-R1a
activity impaired spatial and recognition memory in mice. These observations support a role for the ligand-independent
activity of GHS-R1a in regulating AMPA receptor trafficking under basal conditions and in the context of synaptic
plasticity that underlies learning
Pharmacokinetic Benefits of 3,4-Dimethoxy Substitution of a Phenyl Ring and Design of Isosteres Yielding Orally Available Cathepsin K Inhibitors
Rational structure-based design has yielded highly potent
inhibitors
of cathepsin K (Cat K) with excellent physical properties, selectivity
profiles, and pharmacokinetics. Compounds with a 3,4-(CH<sub>3</sub>O)<sub>2</sub>Ph motif, such as <b>31</b>, were found to have
excellent metabolic stability and absorption profiles. Through metabolite
identification studies, a reactive metabolite risk was identified
with this motif. Subsequent structure-based design of isoteres culminated
in the discovery of an optimized and balanced inhibitor (indazole, <b>38</b>)
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Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate
The widespread emergence of Plasmodium falciparum (Pf) strains resistant to frontline agents has fuelled the search for fast-acting agents with novel mechanism of action. Here, we report the discovery and optimization of novel antimalarial compounds, the triaminopyrimidines (TAPs), which emerged from a phenotypic screen against the blood stages of Pf. The clinical candidate (compound 12) is efficacious in a mouse model of Pf malaria with an ED99 <30 mg kg−1 and displays good in vivo safety margins in guinea pigs and rats. With a predicted half-life of 36 h in humans, a single dose of 260 mg might be sufficient to maintain therapeutic blood concentration for 4–5 days. Whole-genome sequencing of resistant mutants implicates the vacuolar ATP synthase as a genetic determinant of resistance to TAPs. Our studies highlight the potential of TAPs for single-dose treatment of Pf malaria in combination with other agents in clinical development