The Process from Raw Ingredients to Data

The overall workflow of ADME Tox characterization of lead compounds is typically distributed across multiple departments or functional groups within pharmaceutical companies, often with specialized groups for different assays, analysis and interpretation. A representation of the overall workflow is provided in Figure 1.1. Figure 1.1 A typical DMPK workflow. Requests typically come from the lead optimization group for a set of compounds to be tested in a number of ADME Tox assays. These could be...

Solubility as a Function of pH

The solubilities of weak acids and bases are dependent upon the pKa value(s) of the compound, the pH of the solution and the concentration of any counter ions to the 80 4 Solubility and Aggregation 0.30 0.25 Figure 4.1 Solubility versus pH for a monoprotic weak base. A constant amount of weak base is considered and the pH is adjusted with a strong acid or strong base. pH-Solubility Profile of a Weak Base pH-Solubility Profile of a Weak Base Figure 4.1 Solubility versus pH for a monoprotic weak...

Fragmental Approaches

These methods model the log P by adding the specific contributions of elementary building blocks of a molecule, that is, the chemical monoatomic or multiatomic fragments. The geometrical and topological effects that operate in such a case mean that several correction factors have to be added to the additivity scheme. p-Constant Method The precursor method of Hansch and Fujita 35 consisted in the definition of a hydrophobic substituent constant, pX, for a fragment X, obtained by a comparison...

Unwanted Structural Elements

Substructure filtering is a way to address problems caused by chemical reactivity, which is often related to well defined functional groups such as Michael acceptors, epoxides and acid chlorides 45 . Chemical reactivity often causes low stability -especially when stored as a solution over long periods of time - and hence causes technology compatibility problems. At the same time some toxic effects are related to chemical reactivity. Most important here is the reactivity towards DNA which may...

DMPK Testing Strategies the Process from Data to Decisions

Critical to the success of a DMPK testing strategy is the ability to efficiently make decisions that affect the overall drug discovery process. These decisions are made by stakeholders in multiple core disciplines in multiple departments and affect which compounds are carried on to combinatorial library expansion, medicinal chemistry optimization and further biological testing. Within the profiling department itselfthe ability to deliver critical data to the organization is largely gated by the...

Integrative Risk Assessment

At early phases of drug discovery, such as lead selection, project teams should define or update their target compound profile and consider possible liabilities associated with the selected structure and measure them against activity at the primary target. This is very rarely a single component, and in some cases could be a combination of unwanted features which significantly limits progress. As discussed previously, risk identification is possible by using first line, primary assays for many...

Solubility in Simulated Biological Fluids

As already mentioned, the solubility of compounds can be influenced by the presence of other compounds in the solution. This can simply be an ionic strength effect which results in changes to the activity coefficients or the additional compounds can directly interact with the compound ofinterest and result in complexes or aggregates being formed or salts having lower solubility. The use of simulated biological fluids in the determination of solubilities has not been done extensively. The...

Distribution and Elimination

Drug distribution and elimination are important factors influencing the PK PD relationship. Models and latest advances in drug distribution prediction are reviewed in Chapter 9. Metabolism is a major route of elimination for xenobiotics and 0 10 20 30 40 50 60 70 80 90 100 110 Figure 3.1 Correlation between passive permeability and in vivo BAV in Sprague Dawley rats (N 128). The PAMPA F( ) values in the y-axis were derived from the passive permeability measurements in a PAMPA assay 19 using a...

Automation Islands with Manual Data Upload to a LIMS System

A central LIMS system keeps track of the compounds, layout of plates supplied from compound management and the assays requested for each sample. Scientists track the mapping of samples though the preparation of test plates, sample preparation and analysis with the help of macros (usually programmed in Excel). At the conclusion of the experiment, data is uploaded back into the LIMS system for review and delivery to the requesting scientist. Depending on the degree of...

Empirical Rules and Their Basis

Given the difficulties of developing global statistical models for ADME properties, it is understandable that simple empirical rules are used to predict drug-likeness and to filter unwanted compounds in the lead finding phase of drug discovery. The most prominent rule set is the rule of five of Lipinski 21 but other variants also exist. Such rules have been derived from the analysis of the properties of known drugs, or drug candidates which have been successfully developed into drugs. In...

Concluding Discussions

As we have shown above, it is not trivial to set up drug-likeness filtering rules that are globally valid for chemical structures and all targets. However the application of clogP, PSA and molecular weight filters are synergistically beneficial for technology compatibility, the probability of ligands to match the target and bias towards an oral bioavailability. Therefore, the application of such filters during the assembly of the screening collection is generally recommended, provided the...

Software Data Retrieval Analysis Manipulation and Interpretation

While the sample processing bottleneck is well on the way to being solved, the results analysis component still remains a challenge. A variety of software analysis tools exist to automatically analyze and reduce chromatographs to useful interpretive data. However even with automated analysis software, manual review of the data is often required, not only for situations where the chromatograph cannot be analyzed (poor resolution, inappropriate conditions, carryover, etc.), but for all results,...

Specific Safety Profiling Assays

Profiling for toxic effects of compounds at early phase is one of the most debated territories of drug discovery. Many traditional toxicologists still maintain that this is mission impossible. There are two main arguments to support their views 1. Classic toxicology is to a great extent retrospective. Histopathology performed on animals from acute and chronic toxic dosing gives guidance for further, mechanism-based studies, concentrating on a single molecule. Until recently, this approach has...

HTS log Plog D Determination Based on Microtiterplate Format

Methods have been proposed to miniaturize, speed up and automate the shake-flask approach. The main difficulties in this challenge are the number of time-consuming steps which cannot be totally eliminated and the persistence of well known drawbacks. For example, the mutual saturation and decantation of organic and aqueous phases, or the crucial separation ofthe two phases after shaking which multiplies the manipulations. Automation ofthe process is also difficult due to several...