Drug-eluting embolic transarterial chemoembolization (DEE-TACE) improves the overall survival of hepatocellular carcinoma (HCC), but the agents used are not tailored to HCC. Our patented liposomal ...formulation enables the loading and elution of targeted therapies onto DEEs. This study aimed to establish the safety, feasibility, and pharmacokinetics of sorafenib or regorafenib DEE-TACE in a VX2 model. DEE-TACE was performed in VX2 hepatic tumors in a selective manner until stasis using liposomal sorafenib- or regorafenib-loaded DEEs. The animals were euthanized at 1, 24, and 72 h timepoints post embolization. Blood samples were taken for pharmacokinetics at 5 and 20 min and at 1, 24, and 72 h. Measurements of sorafenib or regorafenib were performed in all tissue samples on explanted hepatic tissue using the same mass spectrometry method. Histopathological examinations were carried out on tumor tissues and non-embolized hepatic specimens. DEE-TACE was performed on 23 rabbits. The plasma concentrations of sorafenib and regorafenib were statistically significantly several folds lower than the embolized liver at all examined timepoints. This study demonstrates the feasibility of loading sorafenib or regorafenib onto commercially available DEEs for use in TACE. The drugs eluted locally without release into systemic circulation.
Drug discovery building blocks available commercially or within an internal inventory cover a diverse range of chemical space and yet describe only a tiny fraction of all chemically feasible ...reagents. Vendors will eagerly provide tools to search the former; there is no straightforward method of mining the latter. We describe a procedure and use case in assembling chemical structures not available for purchase but that could likely be synthesized in one robust chemical transformation starting from readily available building blocks. Accessing this vast virtual chemical space dramatically increases our curated collection of reagents available for medicinal chemistry exploration and novel hit generation, almost tripling the number of those with 10 or fewer atoms.
We report here the identification and optimization of a novel series of potent GlyT1 inhibitors. A ligand design campaign that utilized known GlyT1 inhibitors as starting points led to the ...identification of a novel series of pyrrolo3,4-cpyrazoles amides (21–50) with good in vitro potency. Subsequent optimization of physicochemical and in vitro ADME properties produced several compounds with promising pharmacokinetic profiles. In vivo inhibition of GlyT1 was demonstrated for select compounds within this series by measuring the elevation of glycine in the cerebrospinal fluid (CSF) of rats after a single oral dose of 10 mg/kg. Ultimately, an optimized lead, compound 46, demonstrated in vivo efficacy in a rat novel object recognition (NOR) assay after oral dosing at 0.1, 1, and 3 mg/kg.
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A strategy to conformationally restrain a series of GlyT1 inhibitors identified potent analogs that exhibited slowly interconverting rotational isomers. Further studies to address ...this concern led to a series of azetidine-based inhibitors. Compound 26 was able to elevate CSF glycine levels in vivo and demonstrated potency comparable to Bitopertin in an in vivo rat receptor occupancy study. Compound 26 was subsequently shown to enhance memory in a Novel Object Recognition (NOR) behavioral study after a single dose of 0.03 mg/kg, and in a contextual fear conditioning (cFC) study after four QD doses of 0.01–0.03 mg/kg.
An unprecedented amount of parallel synthesis information was accumulated within Pfizer over the past 12 years. This information was captured by an informatics tool known as PGVL (Pfizer Global ...Virtual Library). PGVL was used for many aspects of drug discovery including automated reactant mining and reaction product formation to build a synthetically feasible virtual compound collection. In this report, PGVL is discussed in detail. The chemistry information within PGVL has been used to extract synthesis and design information using an intuitive desktop Graphic User Interface, PGVL Hub. Several real-case examples of PGVL are also presented.
Uncovering useful lead compounds from a vast virtual library of synthesizable compounds continues to be of tremendous interest to pharmaceutical researchers. Here we present the concept of Basis ...Products (BPs), a new and broadly applicable method for achieving efficient selections from a combinatorial library. By definition, Basis Products are a strategically selected subset of compounds from a potentially very large combinatorial library, and any compound in a combinatorial library can represented by its BPs. In this article we will show how to use BP docking scores to find the top compounds of a combinatorial library. Compared with the brute-force docking of an entire virtual library, docking with BPs are much more efficient because of the substantial size reduction, saving both time and resources. We will also demonstrate how BPs can be used for property-based combinatorial library designs. Furthermore, BPs can also be considered as fragments carrying chemistry knowledge, hence they can potentially be used in combination with any fragment-based design method. Therefore, BPs can be used to integrate combinatorial design with structure-based design and/or fragment-based design. Other potential applications of BPs include lead hopping and consensus core building, which we will describe briefly as well in this report.
In previous research, Hilvert and co-workers developed an antibody which catalyzes the decomposition of a nitrobenzisoxazole with a rate >108 times faster than the acetate-catalyzed reaction in ...water. Quantum mechanical calculations were carried out on a model system, the reaction of isoxazole with formate. The orientation of the carboxylate group has a significant effect on the rate. Complexation of the formate base by one water retards the reaction by approximately 5 kcal/mol; hence desolvation of the catalytic base could account for as much as four orders of magnitude in reaction rate. It was also determined that hydrogen-bonding to the forming oxide could potentially lead to greater rate acceleration. The gas phase activation barriers predict that water is the most effective general acid, lowering the activation energy by 9.5 kcal/mol. Methanol and formic acid are also effective, lowering the activation energy by 7.5 and 7.8 kcal/mol, respectively. Our calculations suggest that the combined effects of proper base orientation and acid catalysis could lead to an additional factor of 105−106 increase in rate acceleration. Based on these results, various new haptens were proposed. Each was quantitatively assessed for similarity with the located transition states to predict their potential as successful haptens.
The immunological response produces amino acid residues in the variable regions of antibodies to give tight binding of the antigen. When a hapten closely resembles the transition state of a reaction, ...the antibody binding site may also bind the transition state strongly, resulting in antibody catalysis. During the last ten years, there have been many brilliant demonstrations of hapten-induced production of antibody catalysts. We demonstrate a theoretical method to explore the relationship between optimum binding of a hapten and the catalytic groups which cause acceleration, and show how this method was used to predict which reaction a catalytic antibody would catalyze when confronted with a new substrate. (DBO)
In chapter 1, calculations on the energetic preference for the 5-exo and 6-endo epoxide openings of protonated trans-4,5-epoxyhexan-1-ol are performed. The 1.9 kcal/mol preference for the furan ...product agrees well with the experimentally derived product ratio of 95:5, and agrees with Baldwin's Rules prediction for the 5-exo opening to be favored over the 6-endo opening. Through transition state analysis and the study of interactions of stabilizing groups with an N-oxide hapten, we were able to determine that the location of charged atoms in the hapten, rather than geometric factors, is the key to the success of the antibody. In chapter 2 we extended the work in chapter 1. We studied the energetics for the epoxide openings of cis- and trans-3,4-epoxypentan-1-ol, cis-4,5-epoxyhexan-1-ol, and cis- and trans-5,6-epoxyheptan-1-ol. In 4-exo versus 5-endo openings, all results favor the 5-membered product in greater than 99:1 preference. In the 5-exo versus 6-endo study the 5-exo product is favored by 3.6 kcal/mol, and in the 6-exo versus 7-endo openings both cis and trans epoxides were found to favor the 6-exo opening by 2.6 kcal/mol. Theozyme calculations on the 6-exo versus 7-endo trans-epoxide openings found a 5.0 kcal/mol preferential stabilization for the 7-endo process. Chapter 3 is a study of the base-catalyzed opening of isoxazole, the various factors contributing to catalysis of the reaction, and the prediction of possible haptens based on transition state analysis. The importance of several catalytic effects were estimated and discussed. Examination of transition states and their interaction with stabilizing groups led to the proposition of several potentially potent haptens for antibody production. In Chapter 4 an MM3 force field for the lactonization reaction was developed. Parameterization was based on ab initio calculations on the transition state of syn and anti attack of acetate on ethyl bromide. The efficacy of the force field was then tested against experimental data for the cyclization of 5- to 23-membered lactones. A linear relationship was found between calculated and experimental $\rm\Delta G\ddagger.$ New MM3 parameters for esters and acids were developed for implementation into the MM3 force field.
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