Development of the telescoped flow Pd-catalyzed aerobic alcohol oxidation/reductive amination sequence in the synthesis of new phosphatidylinositide 3-kinase inhibitor (CPL302415).

Herein, we describe a two-step sequential flow synthesis: Pd-catalyzed aerobic oxidation to an aldehyde 2, which is then converted by reductive amination in H-Cube® PRO into CPL302415 (3). CPL302415 is our new PI3Kδ inhibitor, which is now under evaluation for the treatment of systemic lupus erythematosus. The process was optimized using the DoE approach and generalized to other biologically active derivatives of CPL302415.

Quality by Design (QbD) and Design of Experiments (DOE) as a Strategy for Tuning Lipid Nanoparticle Formulations for RNA Delivery.

The successful development of nonviral delivery systems for nucleic acids has been reported extensively over the past years. Increasingly employed to improve the delivery efficiency and therapeutic efficacy of RNA are lipid nanoparticles (LNPs). Many of the various critical formulation parameters can affect the quality attributes and effectiveness of these nano-formulations.

Tuning the Biological Activity of PI3K Inhibitor by the Introduction of a Fluorine Atom Using the Computational Workflow.

As a member of the class I PI3K family, phosphoinositide 3-kinase (PI3K) is an important signaling biomolecule that controls immune cell differentiation, proliferation, migration, and survival. It also represents a potential and promising therapeutic approach for the management of numerous inflammatory and autoimmune diseases. We designed and assessed the biological activity of new fluorinated analogues of CPL302415, taking into account the therapeutic potential of our selective PI3K inhibitor and fluorine introduction as one of the most frequently used modifications of a lead compound to further improve its biological activity.

The design of experiments (DoE) in optimization of an aerobic flow Pd-catalyzed oxidation of alcohol towards an important aldehyde precursor in the synthesis of phosphatidylinositide 3-kinase inhibitor (CPL302415).

Herein, we describe the development of a green, scalable flow Pd-catalyzed aerobic oxidation for the key step in the synthesis of CPL302415, which is a new PI3K inhibitor. Applying this environmental-friendly, sustainable catalytic oxidation we significantly increased product yield (up to 84%) and by eliminating of workup step, we improved the waste index and E factor (up to 0.13) in comparison with the stoichiometric synthesis.

Implementation of QbD Approach to the Development of Chromatographic Methods for the Determination of Complete Impurity Profile of Substance on the Preclinical and Clinical Step of Drug Discovery Studies.

The purpose of this work was to demonstrate the use of the AQbD with the DOE approach to the methodical step-by-step development of a UHPLC method for the quantitative determination of the impurity profile of new CPL409116 substance (JAK/ROCK inhibitor) on the preclinical and clinical step of drug discovery studies. The critical method parameters (CMPs) have been tested extensively: the kind of stationary phase (8 different columns), pH of the aqueous mobile phase (2.6, 3.

Design, Synthesis, and Development of Pyrazolo[1,5-]pyrimidine Derivatives as a Novel Series of Selective PI3K Inhibitors: Part II-Benzimidazole Derivatives.

Phosphoinositide 3-kinase (PI3K) is the family of lipid kinases participating in vital cellular processes such as cell proliferation, growth, migration, or cytokines production. Due to the high expression of these proteins in many human cells and their involvement in metabolism regulation, normal embryogenesis, or maintaining glucose homeostasis, the inhibition of PI3K (especially the first class which contains four subunits: , , , ) is considered to be a promising therapeutic strategy for the treatment of inflammatory and autoimmune diseases such as systemic lupus erythematosus (SLE) or multiple sclerosis. In this work, we synthesized a library of benzimidazole derivatives of pyrazolo[1,5-]pyrimidine representing a collection of new, potent, active, and selective inhibitors of PI3K, displaying IC values ranging from 1.

Dose-linearity of the pharmacokinetics of an intravenous [ C]midazolam microdose in children.

Aims: Drug disposition in children may vary from adults due to age-related variation in drug metabolism. Microdose studies present an innovation to study pharmacokinetics (PK) in paediatrics; however, they should be used only when the PK is dose linear. We aimed to assess dose linearity of a [ C]midazolam microdose, by comparing the PK of an intravenous (IV) microtracer (a microdose given simultaneously with a therapeutic midazolam dose), with the PK of a single isolated microdose.

CE method for the in-process control of the synthesis of active substances conjugated with gold nanoparticles.

A fast capillary electrophoresis method was developed and validated for the in-process control (IPC) of the synthesis of active substances (APIs) with gold nanoparticles (AuNPs). The capillary electrophoresis method was key to ensure that the reaction step conducted in order to obtain AuNP and API conjugates will produce the expected product without the presence of free APIs, which is a critical parameter determining the quality of the synthetic material. Capillary electrophoresis was performed using uncoated fused-silica capillaries with the effective length of 40cm, 50μm i.

Synthesis and characterization of genistein conjugated with gold nanoparticles and the study of their cytotoxic properties.

Gold nanoparticles conjugated with drug substances are used in diagnostics and therapies. Apart from the combinations involving gold nanoparticles conjugated with drug substances through linkers, a direct bonding is also known. In our paper the example of such a direct bonding between gold nanoparticles and genistein (AuNPs-GE) is presented.

Simultaneous determination of the counter ion and possible impurity from the synthetic route in the pharmaceutical substance prasugrel hydrochloride.

A fast and selective capillary electrophoresis method was developed and validated for the simultaneous determination of the hydrochloride and acetic acid content in prasugrel hydrochloride. Because of the poor chromophore, the indirect detection was chosen. Among different compositions studied as the background electrolyte, the pyromellitic acid with diethylamine (DEA) and myristyltrimethylammonium bromide (TTAB) was chosen.

Synthesis and crystal structure of anhydrous analog of 1,25-dihydroxyvitamin d3.

As predicted by single crystal X-ray crystallography, and contrary to the reported suggestions, the anhydrous form of calcipotriol, a therapeutically important vitamin D analog, was found stable enough to be used as an active pharmaceutical ingredient. The crystal and molecular structure of calcipotriol anhydrate was solved and refined using single crystal X-ray diffraction. The analog was obtained by a novel convergent synthesis from the vitamin D C-22 sulfone, as an advanced intermediate and a side-chain fragment.

Validation of GC method for quantitative determination of residual 2-(2-chloroethoxy)ethanol (CEE) and N-methyl-2-pyrrolidinone (NMP) in pharmaceutical active substance.

The gas chromatography method with direct injection for quantitative determination of residual nonvolatile solvents such as 2-(2-chloroethoxy)ethanol (CEE) and N-methyl-2-pyrrolidinone (NMP) in quetiapine--the pharmaceutical active substance has been validated. Validation was performed according to the requirement of ICH validation guidelines Q2A and Q2B. Specificity, precision, accuracy, linearity, limits of detection and quantitation and robustness were determined and excellent results were obtained.

Separation of perfluorocarboxylic acids using capillary electrophoresis with UV detection.

A capillary electrophoretic method with UV detection for separation and quantitation of perfluorocarboxylic acids (PFCAs) from C6-PFCA to C12-PFCA has been developed. The optimization of measurement conditions included the choice of the most appropriate type and concentration of buffer in the background electrolyte (BGE), as well as the type and the content of an organic modifier. The optimal separation of investigated PFCAs was achieved with 50 mM phosphate buffer and 40% isopropanol in the BGE using direct UV detection.