Alkyl Azetidines Via <i>Batch</i> and <i>Flow</i> Photochemistry

Organic Letters · 2025-04-04 · 8 citations

Alkyl azetidines have been prepared by photochemical modifications of azetidine-2-carboxylic acids in batch and in flow. The reaction has been realized in milligram, gram, and even multigram quantities. The obtained azetidines are valuable building blocks for drug discovery.

Novel O-methylpyrimidine prodrugs of phenolic compounds bioactivated by aldehyde oxidase: Enhancing metabolic stability against first-pass conjugative metabolism in the intestine

Drug Metabolism and Disposition · 2025-03-05 · 1 citations

Kilo-Scale-Enabled Route toward PF-07907063, a Type II Brain Penetrant cMET Inhibitor

Organic Process Research & Development · 2025-04-07

New synthetic methodologies that access complex saturated building blocks enable the synthesis of drug molecules with unique properties. Here, we report collaborative efforts between Pfizer’s Medicinal Chemistry, Medicinal Chemistry Synthesis Development, and Pharmaceutical Sciences Small Molecule (PSSM) groups for the development of kilogram-scale-enabled synthesis of a type II brain penetrant cMET inhibitor, PF-07907063. The chemistry presented herein demonstrates the importance of implementing a green chemistry approach for developing and applying new transformations throughout the drug development pipeline. Specifically, synthetic planning rooted in the 12 Principles of Green Chemistry led to advancements in deoxygenative photoredox-nickel dual catalysis and cross-electrophile nickel catalysis. The final route significantly lowered the process mass intensity (PMI), increased the yield of the final API, and allowed for the purification of key intermediates through crystallization versus purging impurities via column chromatography, among other improvements.

National Weather Service Field Testing of the Flash Flood Severity Index: A Retroactive Analysis from 2018 to 2022

Weather and Forecasting · 2025-05-28 · 1 citations

Abstract Flash flooding continues to be one of the deadliest natural hazards in the United States. Unfortunately, most flood classification systems fall short in conveying flood threat to the public. An interdisciplinary approach is necessary to properly categorize flash flood impacts to improve forecasting techniques and provide effective messaging of life-saving flood information. Furthermore, understanding how each flash flood event compares to another provides the community with a more thorough frame of reference regarding local flood hazards. To address this, a collaborative research endeavor resulted in a simple, damage-based, postevent assessment tool—the Flash Flood Severity Index (FFSI). The five-tiered index debuted in 2016, and National Weather Service (NWS) field testing began in 2018 at a subset of Weather Forecast Offices (WFOs). The initial analysis showed that most flash flood events can be categorized as moderate or serious (FFSI-2 or FFSI-3). This study outlines the details of the field testing and the results of classifying local storm reports (LSRs) with FFSI. Links between FFSI and flash flood warning (FFW) impact-based warning (IBW) tags were also incorporated. Results show that there are some disparities between the severity of the flash flood based on FFSI categorization and the IBW tags assigned to the associated FFWs. As the inventory of events grows, collaborators aim to further develop the classification system, expand testing across additional WFOs and other climate regions, and explore the potential for improving flash flood forecasting and messaging techniques.

Real-time visualization of epileptic seizures using photoacoustic imaging with a peroxynitrite-responsive manganese(<scp>ii</scp>) texaphyrin

Chemical Science · 2025-01-01 · 4 citations

fluctuations, offering biochemical insights into epilepsy pathogenesis. By integrating deep-tissue imaging with neurochemical monitoring, this method lays the foundation for potential advances in epilepsy management and treatment.

An Approach to Alkyl Azetidines for Medicinal Chemistry

ChemRxiv · 2025-02-25 · 1 citations

Alkyl azetidines have been prepared by photochemical modifications of azetidine-2-carboxylic acids in batch and in flow. The reaction has been realized in mg-, g-, and even multigram quantities. The obtained azetidines are valuable building blocks for drug discovery.

CCDC 2288552: Experimental Crystal Structure Determination

The Cambridge Structural Database · 2024-01-07

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

CCDC 2288553: Experimental Crystal Structure Determination

The Cambridge Structural Database · 2024-01-07

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Discovery of Pyrazolopyrazines as Selective, Potent, and Mutant-Active MET Inhibitors with Intracranial Efficacy

Journal of Medicinal Chemistry · 2024-08-01 · 4 citations

Mesenchymal-epithelial transition factor (MET) is a receptor tyrosine kinase that serves a critical function in numerous developmental, morphogenic, and proliferative signaling pathways. If dysregulated, MET has been shown to be involved in the development and survival of several cancers, including non-small cell lung cancer (NSCLC), renal cancer, and other epithelial tumors. Currently, the clinical efficacy of FDA approved MET inhibitors is limited by on-target acquired resistance, dose-limiting toxicities, and less than optimal efficacy against brain metastasis. Therefore, there is still an unmet medical need for the development of MET inhibitors to address these issues. Herein we report the application of structure-based design for the discovery and development of a novel class of brain-penetrant MET inhibitors with enhanced activity against clinically relevant mutations and improved selectivity. Compound 13 with a MET D1228N cell line IC50 value of 23 nM showed good efficacy in an intracranial tumor model and increased the median overall survival of the animals to 100% when dosed orally at 100 mg/kg daily for 21 days.

Cyclopentadienyl capped thorium(<scp>iv</scp>) porphyrinoid complex

Chemical Communications · 2023-12-22

The reaction between Th(IV) dipyriamethyrin dichloride and sodium cyclopentadienyl (Cp) results in the formation of a cyclopentadienyl capped thorium dipyriamethyrin complex, which to our knowledge represents the first expanded porphyrin f-element Cp complex.