Physicochemical property optimization

Compound optimization in early- and late-phase drug discovery is covered, emphasizing physicochemical properties, in vitro absorption, metabolism and in vivo animal pharmacokinetic methodologies. 

Partial Least Squares (PLS) regression (Section 35.7) is one of the more recent advances in QSAR which has led to the now widely accepted method of Comparative Molecular Field Analysis (CoMFA). This method makes use of local physicochemical properties such as charge, potential and steric fields that can be determined on a three-dimensional grid that is laid over the chemical stmctures. The determination of steric conformation, by means of X-ray crystallography or NMR spectroscopy, and the quantum mechanical calculation of charge and potential fields are now performed routinely on medium-sized molecules [10]. Modem optimization and prediction techniques such as neural networks (Chapter 44) also have found their way into QSAR. 

In a second example of the identification of IKK(3 inhibitor leads (termed IKK2 in this paper), Baxter et al. [54] report on the optimization of enzyme and cellular potency, physicochemical properties, ADME properties, and PK. This group targets... 

CXCR2 is a member of the CXC family of chemokine receptors. IL-8 activates this receptor, and an antagonist would potentially be useful for the treatment of inflammatory diseases. Baxter et al. [58] describe the parallel optimization of binding and functional potency, physicochemical properties, ADME properties, and PK. The thiol of the HTS hit was varied with typical replacements (i.e., OH, NH2, SMe, NHAc, etc.), but this only led to inactive compounds. Variation of the substituent at N(2) showed that a benzyl moiety was required (Ph, Me substituents gave inactive compounds). Variation of the C(5) substituent showed that -substituents produced optimal activity. The optimized lead has substantially improved CXCR2 binding and functional activity as well as an excellent PK profile (Scheme 13). 

CDK2 is involved with controlling normal cell proliferation. Disregulation in cancer makes this a good antitumor target. Pevarello et al. [62] describe the parallel optimization of enzyme inhibition potency, cellular activity, physicochemical properties, and PK. A low MW hit (MW = 201) was specifically selected with the... 

The optimized drug product may be viewed as a drug-delivery system for the one or more drugs that it contains. The goal of this drug-delivery system is to release the drug(s) to produce the maximum simultaneous safety, effectiveness, and reliability, as depicted in Fig. 9. Various physicochemical product properties that influence the quality features of safety, effectiveness, and reliability are shown in Table 6. Some physicochemical properties can affect two or all three quality features of Fig. 9. For example, consider chemical stability. As a drug decomposes, if the... 

Clearly the physicochemical properties of a drug are a decisive factor in its overall activity. Where possible, molecular structures should be optimized to obtain best clinical performance. Rarely does an oral drug have physicochemical features suitable for topical or transdermal therapy, and it can take a great deal of systematic research to identify where the best balance of activity and permeability lies. Experience with corticosteroids suggests that as much as a 100-fold improvement in clinical activity may be attainable through molecular design, for today s most potent topical corticosteroids are more active than hydrocortisone by a factor at least this large. 

An important part of the optimization process of potential leads to candidates suitable for clinical trials is the detailed study of the absorption, distribution, metabolism and excretion (ADME) characteristics of the most promising compounds. Experience has learned that physico-chemical properties play a key role in drug metabolism and pharmacokinetics (DMPK) [1-3]. As an example, physicochemical properties relevant to oral absorption are described in Fig. 1.1. It is important to note that these properties are not independent, but closely related to each other. 

This chapter will summarize recent developments regarding the role of physicochemical properties in safety liability and the emerging use of physicochemical property-based lead optimization using lipophilic ligand efficiency (LLE or LipE). 

An approach that integrated structure-based drug design with physicochemical properties-based approaches to optimizing drug candidate... 

Two papers described the optimization of LLE and physicochemical properties in a series of pyrazole HTV nonnucleoside reverse transcriptase inhibitors (NNRTIs) and the selection of lersivirine (6) as a development candidate [15,16]. The early lead (7) was relatively lipophilic (clogP = 4.3), rapidly metabolized in human liver microsomes and had an LLE of only 1.9 [pIC50 (HIV RT) - clogP] [15]. An optimization program targeting increased LLE in less lipophilic compounds of low MW (to... 

Examples of the application of strategies based on increasing LLE or LipE and optimizing physicochemical properties as key components of medicinal chemistry programs that delivered clinical development candidates have begun to be described in the last year or so. It remains to be seen whether the hoped for reduction in compound attrition that this approach seeks to achieve will be realized, as it is early days. 

The next section describes the utilization of //PLC for different applications of interest in the pharmaceutical industry. The part discusses the instrumentation employed for these applications, followed by the results of detailed characterization studies. The next part focuses on particular applications, highlighting results from the high-throughput characterization of ADMET and physicochemical properties (e.g., solubility, purity, log P, drug release, etc.), separation-based assays (assay development and optimization, real-time enzyme kinetics, evaluation of substrate specificity, etc.), and sample preparation (e.g., high-throughput clean-up of complex samples prior to MS (FIA) analysis). 

Libraries of hundreds to thousands of spatially separate inhibitors have been prepared and screened to identify small molecule inhibitors of the human protease cathepsin D and the essential malarial proteases, plasmepsins I and II. The best inhibitors do not incorporate any amino adds and possess high affinity (Kj<5 nM).1241 Furthermore, these lead compounds were optimized by combinatorial methods for good physicochemical properties and minimal binding to human serum albumin. The optimized inhibitors effectively block cathepsin D-mediated proteolysis in human hippocampyl slices and are currently being used to evaluate the therapeutic potential of cathepsin D inhibition in the treatment of Alzheimer s disease. Additionally, the plasmepsin inhibitors serve as promising leads for the treatment of malaria. 

Having established the basic features (property prediction and optimization model) for the CAMD-based methodology, the chapter focuses on three examples of a specific implementation of the methodology - the replacement of solvents that are in the production line of many industrial enterprises. The replacement solvents must exhibit the desired environmental and physicochemical properties and also be environmentally more friendly than the solvent they are replacing. 

Sample application is a decisive step in TLC measurements especially in quantitative analyses. The preparative or analytical character of the separation and the volume and physicochemical properties of the sample solution influence equally the mode of sample application. The concentration of the analyte(s) of interest in the sample frequently determines the volume to be applied on the TLC plate a relatively low concentration of analyses requires a high sample volume. Samples containing analyses liable to oxidation have to be applied in a nitrogen atmosphere. Samples can be applied onto the plates either in spots or in bands. It has been proven that the application of narrow bands results in the best separation. The small spot diameter also improves the performance of TLC analysis. The spot diameter has to be lower than 3 mm and 1 mm for classical TLC and HPTLC, respectively. It has been further established that the distance between the spot of the analyte and the entry of the mobile phase also exerts a marked impact on the efficiency of the separation process, the optimal distance being 10 and 6 mm for TLC and HPTLC plates, respectively. 

---