7196 research outputs found
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Using a Johnson-Claisen Rearrangement Strategy to Construct Azaindoles – A Streamlined and Concise Route for the Commercial Process of Fevipiprant
No full textAbstract: A novel and concise synthesis towards DP2 receptor antagonist Fevipiprant (NVS-QAW039) was developed. The initial research route was suffering from lengthy access to the functionalized 7-aza-indole core followed by a low selective N(1)-alkylation with the benzyl side chain. These limitations were overcome by introducing the side chain early via reductive amination between the functionalized aldehyde and 2-amino-3-bromopyridine. Sonogashira coupling with prop-2-yn-1-ol introduces the 3 missing carbon atoms to build the 7-aza-indole core and sets the stage for the innovative Johnson-Claisen key step. Reaction of the advanced propargylic alcohol derivative with trimethyl orthoacetate leads to a reactive allene intermediate that spontaneously and selectively cyclizes to the 7-aza-indole QAW039-methly ester. QAW039 is isolated after ester saponification. Selectivity, yield, and ecological footprint of the new synthesis were significantly improved, and scalability was demonstrated
Micelle enabled C(sp2)–C(sp3) cross-electrophile coupling in water via synergistic nickel and copper catalysis†
No full textA robust and sustainable C(sp2)-C(sp3) cross- electrophile coupling was developed via nickle/copper synergistic catalysis under micellar conditions. This protocol provided a general method to access alkylated arenes with good to excellent yields in very large scale
A New Dioxazolone for the Synthesis of 1,2-Aminoalcohols via Iridium(III)-Catalyzed C(sp3)–H Amidation
No full textVicinal aminoalcohols are widespread structural motifs in bioactive molecules. We report the development of a new dioxazolone reagent containing a p-nitrophenyldifluoromethyl group, which 1. displays a good safety profile; 2. shows a remarkably high reactivity in the oxime-directed iridium(III)-catalyzed amidation of unactivated C(sp3)–H bonds; 3. leads to amide products which can be hydrolyzed under mild conditions. The amidation reaction is mild, general and compatible with both primary C–H bonds of tertiary and secondary alcohols, as well as secondary C–H bonds of cyclic secondary alcohols. This method provides an easy access to free 1,2-aminoalcohols after efficient and mild cleavage of the oxime directing group and activated amide
Continuous Capture scale down model comparison of a continuous and a discrete approach
No full textIn continuous pharmaceutical manufacturing, consisting of a perfused batch fermentation and integrated continuous downstream processing (DSP), the continuous capture is the linking unit operation. For the development of this unit operation, scale-down models (SDMs) are crucial, whereas discrete, non-continuous SDMs are preferred over continuous SDM due to their simplistic nature, reduced material consumption, and shorter operation time. The results presented in this study show the suitability of a discrete SDM approach, compared to a continuous SDM for a continuous protein A purification step
Toward best practice in cancer mutation detection with whole-genome and whole-exome sequencing.
No full textClinical applications of precision oncology require accurate tests that can distinguish true cancer-specific mutations from errors introduced at each step of next-generation sequencing (NGS). To date, no bulk sequencing study has addressed the effects of cross-site reproducibility, nor the biological, technical and computational factors that influence variant identification. Here we report a systematic interrogation of somatic mutations in paired tumor-normal cell lines to identify factors affecting detection reproducibility and accuracy at six different centers. Using whole-genome sequencing (WGS) and whole-exome sequencing (WES), we evaluated the reproducibility of different sample types with varying input amount and tumor purity, and multiple library construction protocols, followed by processing with nine bioinformatics pipelines. We found that read coverage and callers affected both WGS and WES reproducibility, but WES performance was influenced by insert fragment size, genomic copy content and the global imbalance score (GIV; G > T/C > A). Finally, taking into account library preparation protocol, tumor content, read coverage and bioinformatics processes concomitantly, we recommend actionable practices to improve the reproducibility and accuracy of NGS experiments for cancer mutation detection
Risk-Based Pharmacokinetic and Drug-Drug Interaction Characterization of Antibody-Drug Conjugates in Clinical Development: An IQ Consortium Perspective
No full textAntibody-drug conjugates (ADCs) represent a rapidly evolving area of drug development and hold significant promise. To date, nine ADCs have been approved by the FDA and many more are in the early- and late-phase development. These conjugates combine the target specificity of monoclonal antibodies with the anti-cancer activity of small-molecule therapeutics (also referred to as payload). Due to the complex structure, three analytes, namely conjugate, total antibody and unconjugated payload, are typically quantified during drug development, however. the benefits of measuring all 3 analytes at later stages of clinical development are not clear. The cytotoxic payloads, upon release from the ADC, are expected to behave like small molecules. Given the relatively high potency and low systemic exposure of cytotoxic payloads, drug-drug interaction (DDI) considerations for ADCs might be different from traditional small molecule therapeutics. The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium) convened an ADC working group to create an IQ ADC database that includes 26 ADCs with 6 unique payloads. The analyses from IQ ADC database and 9 approved ADCs support the strategy of PK characterization of all three analytes in early-phase development and progressively minimizing the number of analytes to be measured in the late-phase studies. The systemic concentrations of unconjugated payload are usually too low to serve as a DDI perpetrator, however, the potential for unconjugated payloads as a victim still exists. A data-driven and risk-based decision tree was developed to guide the assessment of a circulating payload as a victim of DDI
Continuous Slurry Plug Flow Fe/ppm Pd Nanoparticle-Catalyzed Suzuki-Miyaura Couplings in Water Utilizing Novel Solids Handling Equipment
No full textHerein are reported initial efforts to develop a generally accessible flow process, applying a heterogenous nanocatalyst to aqueous micelle-enabled Suzuki-Miyaura coupling reactions. Also disclosed is a new engineering solution (i.e., a self-draining back pressure regulator), which, when applied, enabled 1.5 hours of continuous operation leading to the production of 20 grams of a pharmaceutical intermediate
Forming Partnerships and Meeting the Needs of Patient Populations
No full textOverview of the Novel Delivery Technology group in TRD. Covering aspects on ideal partnerships and our primary remit to identify new delivery technologies that meet gaps in our technology platforms. Also included is the need tor the technology to offer reduced burden for the patient, care provider and healthcare system
Identification of Bioisosteric Scaffolds using Scaffold Keys
No full textReplacement of a central scaffold in a bioactive molecule by another scaffold with similar structural features (a procedure called sometimes "scaffold hopping") is a classical medicinal chemistry technique used to improve molecular properties and explore novel interesting areas of chemical space. The new scaffolds may be identified by database mining, match in physicochemical properties and often just by applying medicinal chemistry knowledge. In this study a novel method to find bioisosteric scaffolds is described when these are identified using similarity in simple substructure features called Scaffold Keys. Performance of the method is illustrated on several examples and a freely-available web tool https://bit.ly/scaffoldkeys allowing to find bioisosteric scaffold analogs is introduced
