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Automated chiral method screening – Evaluation of generated chromatographic data sets to further optimize screening efficiency
No full textWe set up an automated screening process to routinely test 10 chiral supercritical fluid chromatography (SFC) methods - five columns combined with two co-solvents - as part of a chiral separation lab workflow. Proprietary software tools enabled automated method screening of racemates, parallel evaluation of the resulting chromatograms for enantiomer separation and report generation. This process is largely automated and resulted in an efficient and reliable lab process with a minimum requirement for human intervention. Screenings were conducted on a test set of 756 racemates that were selected with focus on structural variation and on 2667 proprietary samples from lab routines. Statistical analysis revealed that up to 92% of the tested racemic mixtures could be successfully separated with at least one of the tested conditions of the screening. Process efficiency was further increased by identification of optimal method screening sequence, re-definition of the optimal column set and project-specific adaptations considering reduced structural variation of the analytes. This study illustrates the usefulness of consistent chromatographic data sets to accelerate and facilitate the identification of chiral methods to separate enantiomers by automated processing and statistical analysis
Water-Sculpting of a Heterogeneous Nanoparticle Pre-catalyst for Mizoroki-Heck Couplings Under Micellar Catalysis Conditions
No full textFormation of powdery, spherical nanoparticles (NPs) containing ppm levels of palladium ligated by t -Bu3P, derived from FeCl3, upon simple exposure to water undergo a remarkable alteration in their morphology leading to nanorods that catalyze Mizoroki-Heck (MH) couplings. Such NP alteration is general, shown to occur with three unrelated phosphine ligand-containing NPs. Each catalyst has been studied using XPS, EDX, TEM and cryo-TEM analyses. Couplings that rely specifically on NPs containing t -Bu3P-ligated Pd occur under aqueous micellar catalysis conditions between room temperature and 45 °C, and show broad substrate scope. Other key features associated with this new technology include: low residual Pd in the product, recycling of the aqueous reaction medium, and an associated low E Factor. Synthesis of the precursor to galipinine, a member of the Hancock family of alkaloids, is suggestive of potential industrial applications
Legends of allergy and immunology: Jan E. de Vries
No full textJan Egbert de Vries (Figure 1) is a cosmopolitan immunologist and an enthralling mentor with a large track record of innovative achievements in the fields of allergy and immunology. Jan was born in Strijen, a small town located in the Hollands Diep estuary in western Netherlands (NL). He spent his youth in the NL combining his studies with his passion for sports,becoming Dutch champion in decathlon. Shortly after his PhD, and like his fellow countryman Erasmus of Rotterdam, he started a long journey that brought him to France, California, Austria and Switzerland,although never settling in any of the cities he worked.Like Erasmus, he has been since an insatiable scholar ("Non est ulla studiorum satietas") and an inspiring mentor for a large number of students and collaborators
Stability liabilities of biotherapeutic proteins: early assessment as mitigation strategy
No full textIdentification of molecular liabilities and implementation of mitigation strategies are key aspects that need to be considered by pharmaceutical companies developing therapeutic proteins.
In the field of monoclonal antibodies, an efficient and streamlined process known as developability assessment is used for the selection of the “fittest” candidate. Other protein modalities, have in most cases only a limited number of possible candidates, requiring a paradigm change to a concept of candidate enabling. The assessment of liabilities at early project phases with the possibility to re-engineer candidates becomes essential for the success of these projects.
Each protein possesses a unique stability profile resulting from the interplay of conformational, colloidal, chemical and physical stability attributes. All of these attributes strongly depend on external factors. Conformational and colloidal stability profiles of three non-immunoglobulin domain based proteins, namely Carbonic anhydrase, Ovalbumin and Thyroglobulin, and of two monoclonal antibodies were assessed in dependence of solution pH, ionic strength and varying buffering agents. The impact of screened external factors on proteins’ stability attributes varied significantly, indicating presence of molecule specific liabilities. Screening of such a broad space of conditions at early project phases is only feasible using low-material consuming, high-throughput analytical methods as exemplified in this study
Leveraging bile solubilization of poorly water-soluble drugs by rational polymer selection
No full textPoorly water-soluble drugs frequently solubilize into bile colloids and this natural mechanism is key for efficient bioavailability. We tested the impact of pharmaceutical polymers on this solubilization interplay using proton nuclear magnetic resonance spectroscopy, dynamic light scattering, and by assessing the flux across model membranes. Eudragit E, Soluplus, and a therapeutically used model polymer, Colesevelam, impacted the bile-colloidal geometry and molecular interaction. These polymer-induced changes reduced the flux of poorly water-soluble and bile interacting drugs (Perphenazine, Imatinib) but did not impact the flux of bile non-interacting Metoprolol. Non-bile interacting polymers (Kollidon VA 64, HPMC-AS) neither impacted the flux of colloid-interacting nor colloid-non-interacting drugs. These insights into the drug substance/polymer/bile colloid interplay potentially point towards a practical optimization parameter steering formulations to efficient bile-solubilization by rational polymer selection
Efficacy and tolerability of a folic acid derivative of aminopterin in a rat focal model of multiple sclerosis
No full textBackground: Activated macrophages in the experimental model of multiple sclerosis (MS) express folate receptor-β (FR-β), representing a promising target for the treatment of MS. Here, we both evaluated the efficacy of a novel folate-aminopterin construct (EC2319) in a rat focal model of multiple sclerosis (MS) and investigated the utility of 68 Ga-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid-conjugated folate (68Ga-FOL) for assessing inflammatory lesions. In addition, we investigated whether FR-β is expressed in the brain of patients with MS. Methods: Focal delayed-type hypersensitivity experimental autoimmune encephalomyelitis (fDTH-EAE) was induced in 40 Lewis rats; 20 healthy Lewis rats were used as controls. Rats were divided into six groups according to the duration of disease (control, acute, or chronic) and intervention (vehicle versus EC2319). 68Ga-FOL analyses, histology, and immunofluorescence of the brain were performed to evaluate the efficacy of subcutaneously administered EC2319 on lesion development. Immunofluorescence was used to assess FR-β expression in postmortem brain samples from 5 patients with MS and 5 healthy controls. Results: Immunofluorescence and histological analyses revealed significant reductions in FR-β expression (P < 0.05) and lesion size (P < 0.01), as well as improved inducible nitric oxide synthase/mannose receptor C type 1 ratios (P < 0.01) in macrophages and microglia during the chronic but not acute phase of fDTH-EAE in EC2319-treated rats. The uptake of IV-injected 68Ga-FOL in the brain was low and did not differ between the groups, but the in vitro binding of 68Ga-FOL was significantly lower in EC2319-treated rats (P < 0.01). FR-β positivity was observed in chronically active lesions and in normal-appearing white matter in MS brain samples. Conclusions: EC2319 was well tolerated and attenuated inflammation and lesion development in a rat model of a chronic progressive form of MS. Human MS patients have FR-β-positive cells in chronically active plaques, which suggests that these results may have translational relevance
International Harmonization of Nomenclature and Diagnostic Criteria (INHAND): Nonproliferative and Proliferative Lesions of the Dog
No full textThe INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions) Project (www.toxpath.org/inhand.asp) is a joint initiative of the societies of toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying lesions observed in most tissues and organs from the dog used in nonclinical safety studies. Some of the lesions are illustrated by color photomicrographs. The standardized nomenclature presented in this document is also available electronically on the internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous lesions, lesions induced by exposure to test materials, and relevant infectious and parasitic lesions. A widely accepted and utilized international harmonization of nomenclature for lesions in laboratory animals will provide a common language among regulatory and scientific research organizations in different countries and increase and enrich international exchanges of information among toxicologists and pathologists
Late-stage cyanation of aryl/heteroaryl halides using ppm levels of a bidentate phosphine-derived palladacycle in water
No full textEasily accessible and bench stable Xantphos-based palladacycle pre-catalyst can be used for late stage cyanation of highly complex molecules, as well as for a wide variety of aryl and heteroaryl halides possessing sensitive functional groups. The aqueous nanomicelles formed from the commercially available, inexpensive surfactant Brij-30 efficiently act as nanoreactors enabling use of ppm levels of Pd catalysis in water that is efficient, relatively rapid, and far greener than any other existing technology
Selective androgen receptor modulators activate the canonical prostate cancer androgen receptor program and repress cancer growth
No full textProstate cancer (PC) is driven by androgen receptor (AR) activity, a master regulator of prostate development and homeostasis. Frontline therapies for metastatic PC deprive the AR of the activating ligands testosterone (T) and dihydrotestosterone (DHT) by limiting their biosynthesis or blocking AR binding. Notably, AR signaling is dichotomous, inducing growth at lower activity levels, while suppressing growth at higher levels. Recent clinical studies have exploited this effect by administration of supraphysiological concentrations of T, resulting in clinical responses and improvements in quality of life. However, the use of T as a therapeutic agent in oncology is limited by poor drug-like properties as well as rapid and variable metabolism. Here, we investigated the antitumor effects of selective AR modulators (SARMs), which are small-molecule nonsteroidal AR agonists developed to treat muscle wasting and cachexia. Several orally administered SARMs activated the AR program in PC models. AR cistromes regulated by steroidal androgens and SARMs were superimposable. Coregulatory proteins including HOXB13 and GRHL2 comprised AR complexes assembled by both androgens and SARMs. At bioavailable concentrations, SARMs repressed MYC oncoprotein expression and inhibited the growth of castration-sensitive and castration-resistant PC in vitro and in vivo. These results support further clinical investigation of SARMs for treating advanced PC
A study of new exploratory tools, digital technologies and biomarkers to characterize depression
No full textBackground: Digital technologies have the potential to provide objective and precise tools to detect depression-related symptoms. Deployment of digital technologies in clinical research can enable collection of large volumes of clinically relevant data that may not be captured using conventional psychometric questionnaires and patient-reported outcomes. Rigorous methodology studies to develop novel digital endpoints in depression are warranted.
Objective: We conducted an exploratory, cross-sectional study to assess feasibility of several novel digital technologies in subjects with major depressive disorder (MDD) and normal healthy controls. The study aimed at assessing utility and accuracy of the digital technologies as potential diagnostic tools for MDD, as well as correlating digital biomarkers to clinically validated psychometric questionnaires in depression.
Methods: A cross-sectional, non-interventional study of 20 subjects with MDD and 20 normal healthy volunteers was conducted at the Centre for Human Drug Research (CHDR), the Netherlands. Eligible participants attended three in-clinic visits (days 1, 7, and 14), at which they underwent a series of assessments, including conventional clinical psychometric questionnaires and novel digital technologies. Between the visits, there was at-home collection of data through mobile applications. In all, eight digital technologies were evaluated in this study.
Results: Our data analysis was organized by technology – to better understand individual features of various technologies. In many cases, we obtained simple, parsimonious models that have reasonably high diagnostic accuracy and potential to predict standard clinical outcome in depression.
Conclusion: This study generated many useful insights for future methodology studies of digital technologies and proof of-concept clinical trials in depression and possibly other indications