A5101815130- Catalytic Cross-Coupling Reactions
- Chemical Synthesis and Analysis
- Organoboron and organosilicon chemistry
- Crystallization and Solubility Studies
- Synthetic Organic Chemistry Methods
- X-ray Diffraction in Crystallography
- Carbohydrate Chemistry and Synthesis
- Synthesis and Catalytic Reactions
- Chemical Synthesis and Reactions
- Glycosylation and Glycoproteins Research
- Molecular spectroscopy and chirality
- Asymmetric Hydrogenation and Catalysis
- Axial and Atropisomeric Chirality Synthesis
- Catalytic C–H Functionalization Methods
- Sulfur-Based Synthesis Techniques
- Fluorine in Organic Chemistry
- Synthesis of Organic Compounds
- Oxidative Organic Chemistry Reactions
- Innovative Microfluidic and Catalytic Techniques Innovation
- Computational Drug Discovery Methods
- Machine Learning in Materials Science
- Click Chemistry and Applications
- Asymmetric Synthesis and Catalysis
- Cancer therapeutics and mechanisms
- DNA Repair Mechanisms
Pharmaceutical Product Development (India)
2025
AstraZeneca (Brazil)
2025
AstraZeneca (United Kingdom)
2013-2024
TGS (United Kingdom)
2017
Syngenta (United Kingdom)
2006
University of Oxford
2006
Qinetiq (United Kingdom)
2005
University of York
1998-2002
Hertfordshire Community NHS Trust
2002
Roche (United Kingdom)
2002
Epidermal growth factor receptor (EGFR) inhibitors have been used clinically in the treatment of non-small-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a number years. Despite encouraging clinical efficacy with these agents, many resistance develops leading to disease progression. In most cases, this is form T790M mutation. addition, EGFR wild type inhibition inherent agents can lead dose limiting toxicities rash and diarrhea. We describe herein...
High-throughput experimentation (HTE) has revolutionized the pharmaceutical industry, most notably allowing for rapid screening of compound libraries against therapeutic targets. The past decade also witnessed extension HTE principles toward realm small-molecule process chemistry. Today, major companies have created dedicated groups within their development teams, invested in automation technology to accelerate screening, or both. industry's commitment accelerating led innovations space....
pH–rate profiles for aqueous–organic protodeboronation of 18 boronic acids, many widely viewed as unstable, have been studied by NMR and DFT. Rates were pH-dependent, varied substantially between the with rate maxima that over 6 orders magnitude. A mechanistic model containing five general pathways (k1–k5) has developed, together input [B]tot, KW, Ka, KaH, kinetics can be correlated a function pH (1–13) all species. Cyclopropyl vinyl acids undergo very slow protodeboronation, do 3- 4-pyridyl...
Pioneering studies by Kuivila, published more than 50 years ago, suggested ipso protonation of the boronate as mechanism for base-catalyzed protodeboronation arylboronic acids. However, study was limited to UV spectrophotometric analysis under acidic conditions, and aqueous association constants (Ka) were estimated. By means NMR, stopped-flow IR, quenched-flow techniques, kinetics 30 different acids has now been determined at pH > 13 in dioxane 70 °C. Included are all 20 isomers...
ATM inhibitors, such as 7, have demonstrated the antitumor potential of inhibition when combined with DNA double-strand break-inducing agents in mouse xenograft models. However, properties 7 result a relatively high predicted clinically efficacious dose. In an attempt to minimize attrition during clinical development, we sought identify inhibitors low dose (<50 mg) and focused on strategies increase both potency human pharmacokinetic half-life (predominantly through volume distribution)....
Abstract Axially chiral phenols are attractive targets in organic synthesis. This motif is central to many natural products and widely used as precursors to, or directly, ligands catalysts. Despite their utility few simple catalytic methods available for synthesis high enantiopurity. Herein the atropselective acylation of a range symmetric biaryl diols investigated using isothiourea catalysis. Studies on model diol substrate shows that product er observed process result two successive...
The use of N-sulfonyloxy carbamates as reoxidants for the tethered aminohydroxylation (TA) reaction is reported. These new conditions obviate requirement lithium hydroxide and tBuOCl in oxidation mixture. In addition to providing products good yields, catalyst loadings can be reduced just 1 mol % osmium. Moreover, first time, homoallylic alcohols are now viable substrates TA reaction.
While the treatment of gastrointestinal stromal tumors (GISTs) has been revolutionized by application targeted tyrosine kinase inhibitors capable inhibiting KIT-driven proliferation, diverse mutations to this drive resistance established therapies. Here we describe identification potent pan-KIT mutant that can be dosed without being limited tolerability issues seen with multitargeted agents. This effort focused on and optimization an existing scaffold through use structure-based design....
The Garner aldehyde-derived methylene alkene 5 and the corresponding benzyloxycarbonyl compound 25 undergo hydroboration with 9-BBN-H followed by palladium-catalyzed Suzuki coupling reactions aryl vinyl halides. After one-pot hydrolysis-oxidation, a range of known novel nonproteinogenic amino acids were isolated as their N-protected derivatives. These organoborane homoalanine anion equivalents are generated transformed under mild conditions wide functional group tolerance: electron-rich...
Ceralasertib is currently being evaluated in multiple phase I/II clinical trials for the treatment of cancer. Its structure, comprising a pyrimidine core decorated with chiral morpholine, cyclopropyl sulfoximine and an azaindole, makes it challenging molecule to synthesize on large scale. Several features medicinal chemistry early development route make unsuitable long-term commercial manufacture active pharmaceutical ingredient. We describe investigation new improved which introduces moiety...
Process development activities required to develop a robust and scalable synthetic route AZD7594 (1) are disclosed. Included in this paper is the rationale for selection of palladium-mediated Buchwald–Hartwig coupling form key C–N bond. Reaction optimization understanding were performed minimize impurity formation control strategy. The optimized sequence was used manufacture 220 kg clinical trials.
We developed a scalable Suzuki process for the synthesis of lanabecestat (+)-camsylate, an active pharmaceutical ingredient that was recently investigated in Phase III clinical program treatment early Alzheimer's disease. The evolution this culminated with use stable and crystalline diethanolamine boronic ester rapidly hydrolyses under reaction conditions. Herein, we report liberated plays important role catalytic process, supporting evidence equilibrium between unbound bound palladium...
A multidisciplinary approach covering synthetic, physical, and analytical chemistry, high-throughput experimentation experimental design, process engineering, solid-state chemistry is used to develop a large-scale (kilomole) Suzuki-Miyaura process. Working against clear criteria targets, full investigation optimization package described highlighting how why key decisions are made in the development of pharmaceutical processes.
An exploratory investigation into the molecular-level determinants influencing efficient drug loading in PLGA nanoparticles using a nanoprecipitation method.
Two novel routes to C-linked glycosyl amino acids are described; the first involves elaboration of an exo-glycal and subsequent Ramberg–Bäcklund rearrangement a sulfone intermediate give, after functional group manipulation, protected C-glycosyl serine, while second uses hydroboration–Suzuki coupling same produce ultimately corresponding asparagine analogue.
We report the discovery of a novel series 3-cinnoline carboxamides as highly potent and selective ataxia telangiectasia mutated (ATM) kinase inhibitors. Optimization this focusing on potency physicochemical properties (especially permeability) led to identification compound 21, ATM inhibitor (ATM cell IC50 0.0028 μM) with excellent selectivity favorable pharmacokinetics properties. In vivo, 21 in combination irinotecan showed tumor regression SW620 colorectal xenograft model, superior...
In one of our drug development projects, we identified potent KRASG12C inhibitors for treatment cancer. For early preclinical studies, needed a strategy to enable supply two candidates in cost-effective and productive manner. The active pharmaceutical ingredients (APIs) were structurally complex initially obtained via long linear sequences resulting time-consuming manufactures. addition, both comprised biaryl fragment with hindered rotation along the chiral axis. As result, pair stable...
Zirconium- and titanium-mediated diene metallabicyclisation–elimination–functionalisation have been compared, contrasted utilised for the preparation of 3,4-disubstituted 2,3,4-trisubstituted pyrrolidines in high yield excellent stereoselectivity. The zirconium-mediated methodology has employed as key step a partial synthesis (−)-α-kainic acid starting from D-serine, but metallabicyclisation sequence proceeded with poor stereocontrol. By contrast, total L-serine was accomplished using...
Abstract Axially chiral phenols are attractive targets in organic synthesis. This motif is central to many natural products and widely used as precursors to, or directly, ligands catalysts. Despite their utility few simple catalytic methods available for synthesis high enantiopurity. Herein the atropselective acylation of a range symmetric biaryl diols investigated using isothiourea catalysis. Studies on model diol substrate shows that product er observed process result two successive...