Daprodustat is a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor indicated for treating anemia in patients with chronic kidney disease (CKD). This study describes a novel, efficient, and robust kilogram-scale manufacturing process for daprodustat starting from commercially available malonic acid by implementing quality by design (QbD) principles. A novel synthetic approach was adopted for the synthesis of methyl (1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonyl)glycinate by avoiding the use of ethyl isocyanatoacetate and replacing it with methyl glycinate and CDI. To our delight, we achieved a throughput of 76% with over 99% purity for daprodustat, compared to the previously reported throughput of 52%. This approach has enabled us to develop a more environmentally friendly process for synthesizing daprodustat than the prior method.

AbstractDiabetes mellitus, commonly referred to as diabetes, is a persistent medical condition that contributes to a significant global mortality rate and various associated complications in individuals. To address the needs of those diagnosed with type 2 diabetes, the pharmaceutical market offers a range of antidiabetic medications. Among these options, gliflozins stand out as highly efficacious therapeutic agents for the management of type 2 diabetes. These medications inhibit the function of sodium–glucose linked transporter (SGLT) enzymes in the kidneys, effectively halting the reabsorption of sugar and leading to a reduction in the overall glucose load within the bloodstream. This review aims at providing a comprehensive overview of the various syntheses for each of the gliflozin drugs reported in the literature and also summarizes the synthetic advancements in this area to date.1 Introduction2 Synthesis of Gliflozins2.1 Canagliflozin2.2 Dapagliflozin2.3 Ipragliflozin2.4 Empagliflozin2.5 Luseogliflozin2.6 Tofogliflozin2.7 Ertugliflozin2.8 Sotagliflozin2.9 Licogliflozin2.10 Remogliflozin2.11 Henagliflozin2.12 Bexagliflozin2.13 Janagliflozin2.14 Velagliflozin2.15 Sergliflozin Etabonate2.16 Enavogliflozin3 Conclusion

Cabazitaxel 1 is an antineoplastic agent belonging to the taxane class and approved for the treatment of hormone-refractory prostate cancer. During the optimization process of cabazitaxel, six related substances were detected using the gradient high-performance liquid chromatography technique. A thorough study was undertaken to identify, prepare, and control these six related substances. The molecular weights were determined by liquid chromatography-mass spectrometry analysis. Using spectroscopic analysis (high-resolution mass spectrometry (HRMS), infrared (IR), and NMR), the structures were determined as an amino alcohol derivative (CRS-1), 7,10-dimethoxy-10-deacetylbaccatin III (CRS-2), an N-formyl-related substance (CRS-3), 7,10,13-trimethoxy-10-deacetylbaccatin III (CRS-4), a DiBOC-related substance (CRS-5), and a process-related intermediate (CRS-6). The mechanistic aspects of the formation, synthesis, and control strategy of the associated substances were examined in detail.

The stereoselective synthesis of alpha- and beta-C-glycosides isone of the most challenging areas of research in the field of glycoside chemistry. In this review, we summarize the various methods available for stereocontrolled glycosylation and also discuss the predictive mod-els available to explain the stereochemical outcome of six- and five-membered-ring oxocarbenium ions with allyltrimethylsilane nucleophile under Lewis acid conditions

The development of an efficient route for the synthesis of Canagliflozin is reported. The anhydroketopyranose intermediate was isolated as a novel intermediate, which was used to prepare Canagliflozin API in high purity.

Iron-catalyzed Kumada–Corriu cross-coupling was developed for the manufacturing of Aliskiren. The cross-coupled product was purified by using agitated thin film evaporator (ATFE) technique on scale avoiding the use of chromatography. In addition to this, a protocol utilizing sacrificial MeMgCl to achieve the stringent moisture levels required for consistent preparation of Grignard reagent was developed. This allowed successful scale-up of Aliskiren on a 50 Kg scale.

Inherent creativity in synthetic organic chemists is hallucinogenic and found to have potential to impact global healthcare industry incredibly by executing contemporary organometallic strategies to manufacture the products of varied interest. Application of organometallics in chemical industry has intensely perfected the manufacturing of the materials right from trade goods to very personalized medicines without generating significant amount of waste. In pursuit of drug development, two types of challenges are encountered. The first one is related to design of the molecules, and the second is related to the manufacturing of these at commercial scale. Contemporary organometallics in the context of drug development and process research have advanced the toolbox of enabling technologies for addressing these challenges posed during drug development.

Within the spectrum of kinase inhibitors, covalent-reversible inhibitors (CRIs) provide a valuable alternative approach to classical covalent inhibitors. This special class of inhibitors can be optimized for an extended drug-target residence time. For CRIs, it was shown that the fast addition of thiols to electron-deficient olefins leads to a covalent bond that can break reversibly under proteolytic conditions. Research groups are just beginning to include CRIs in their arsenal of compound classes, and, with that, the understanding of this interesting set of chemical warheads is growing. However, systems to assess both characteristics of the covalent-reversible bond in a simple experimental setting are sparse. Here, we have developed an efficient methodology to characterize the covalent and reversible properties of CRIs and to investigate their potential in targeting clinically relevant variants of the receptor tyrosine kinase EGFR.

Kinase inhibitors represent the backbone of targeted cancer therapy, yet only a limited number of oncogenic drivers are directly druggable. By interrogating the activity of 1,505 kinase inhibitors, we found that BRD4-NUT-rearranged NUT midline carcinoma (NMC) cells are specifically killed by CDK9 inhibition (CDK9i) and depend on CDK9 and Cyclin-T1 expression. We show that CDK9i leads to robust induction of apoptosis and of markers of DNA damage response in NMC cells. While both CDK9i and bromodomain inhibition over time result in reduced Myc protein expression, only bromodomain inhibition induces cell differentiation and a p21-induced cell-cycle arrest in these cells. Finally, RNA-seq and ChIP-based analyses reveal a BRD4-NUT-specific CDK9i-induced perturbation of transcriptional elongation. Thus, our data provide a mechanistic basis for the genotype-dependent vulnerability of NMC cells to CDK9i that may be of relevance for the development of targeted therapies for NMC patients.

This presentation will describe how structural biology, molecular pharmacology, and medicinal chemistry studies can be combined with molecular modeling and chemoinformatics analyses for a more accurate description and prediction of structural determinants of protein-ligand binding, functional activity, and selectivity.The challenges and possibilities of structural chemogenomics studies will be discussed, including the integration of large volumes of heterogeneous pharmacological and chemical data for different protein targets and the development of structure-based virtual screening and computer-aided drug design approaches to discover novel small molecule ligands with well defined functional activity and protein selectivity profiles.The potential of molecular dynamics simulation methods to complement hybrid structural biology studies will be demonstrated for the investigation the mechanisms of conformational selection and protein-ligand binding kinetics.In the final part of the presentation structural protein-ligand interaction databases will be described that link structure-based protein-ligand interaction maps to protein ligand topology and can be used as structural chemogenomics tools to navigate medicinal chemistry space.

The cytosolic Ser/Thr kinase TBK1 was discovered to be an essential element in the mediation of signals that lead to tumor migration and progression. These findings meet the need for the identification of novel tool compounds and potential therapeutics to gain deeper insights into TBK1 related signaling and its relevance in tumor progression. Herein, we undertake the activity-based screening for unique inhibitors of TBK1 and their subsequent optimization. Initial screening approaches identified a selection of TBK1 inhibitors that were optimized using methods of medicinal chemistry. Variations of the structural characteristics of a representative 2,4,6-substituted pyrimidine scaffold resulted in improved potency. Prospective use as tool compounds or basic contributions to drug design approaches are anticipated for our improved small molecules.

The clinical success of covalent kinase inhibitors in the treatment of EGFR-dependent non-small cell lung cancer (NSCLC) has rejuvenated the appreciation of reactive small molecules. Acquired drug resistance against first-line EGFR inhibitors remains the major bottleneck in NSCLC and is currently addressed by the application of fine-tuned covalent drugs. Here we report the design, synthesis and biochemical evaluation of a novel class of EGFR inhibitors with a covalent yet reversible warhead. A series of WZ4002 analogs, derived from anilinopyrimidine and 3-substituted-2-cyanoacrylamide scaffolds, exhibit strong and selective inhibitory activity against clinically relevant EGFRL858R and EGFRL858R/T790M.

Synthesis of decahydro-1H-benzo[f]chromene system using intermolecular Diels-Alder reaction has been carried out for the construction of skeleton of terpendole class of terpenoids.

In this Letter, we describe the novel synthetic approach to the tricyclic core of (±)-galanthamine from the easily available starting material isovanillin.

The palladium-catalyzed [10% Pd(OH)(2)/C] reduction of N-(tert-butoxycarbonyl)indoles to the corresponding N-(tert-butoxycarbonyl)indolines is described. Polymethylhydrosiloxane was used as reducing agent and the reaction proceeded smoothly at room temperature in short reaction times giving the products in good yields.

SYNTHESIS 2007, No. 10, pp 1509–1512xx.xx.2007 Advanced online publication: 02.05.2007 DOI: 10.1055/s-2007-966029; Art ID: Z04207SS © Georg Thieme Verlag Stuttgart · New York Abstract: The palladium-catalyzed [10% Pd(OH)2/C] reduction of N-(tert-butoxycarbonyl)indoles to the corresponding N-(tertbutoxycarbonyl)indolines is described. Polymethylhydrosiloxane was used as reducing agent and the reaction proceeded smoothly at room temperature in short reaction times giving the products in good yields.

1,3-Dipolar cycloaddition of in situ generated azometh-ine ylides to electron deficient olefins catalyzed tris(pentafluorophenyl)borane is described.