The Physicochemical Challenge

Triple blockers of ACE, NEP and ECE-1, such as 64, may produce a beneficial synergistic effect. 

FIGURE 27.15 The median MW and cLogP values for DMLs are higher than those for oral drugs or a general set of preclinical compounds from Organon s SCOPE database.  

CHAPTER 27 Multi-target Drugs Strategies and Challenges for Medicinal Chemists 

FIGURE 27.16 A example of a fused DML with a high MW and low oral absoiption. 

FIGURE 27.17 Median MW of DMLs derived via framework combination and screening compared to a general set of preclinical compounds. 

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Morphy, R. and Rankovic, Z. (2006) The physicochemical challenges of designing multiple ligands. Journal of Medicinal Chemistry, 49 (16), 4961 970. 

Seventy years later, this theory largely holds true, although periodically challenged [67, 68]. Observation of transmembrane permeability of ionic species was initially explained by the formation of neutral ion-pair [69, 70]. A comprehensive review of the physicochemical properties influencing permeation has been written by Malkia et al. [5]. The reality is that, despite many studies, the effect of ionization on permeation is still a matter of discussion and active research. In contrast, it became clear that bulk-phase partitioning measurements are not adequate to describe bilayer partitioning [71-73]. 

The process of combining cyanine and squaraine dyes by encapsulation, or covalent or noncovalent attachment with macrocyclic hosts, macromolecules, and micro- or nano-particles is a promising way to design novel probes and labels with substantially improved properties and for the development of advanced fluorescence-based assays. Nevertheless, the physicochemical properties of these dye-compositions are strongly dependent on the dye structure as well as the nature of the host macrocycle, macromolecule, or particle. Finally, development of new methods to synthesize these tracers can also be considered a challenging task. 

It has been a continuous effort to improve the physicochemical, fimc-tional, sensory, and biological properties of psyllium for promoting its food utilization and enhancing its safety. It is a great challenge to disperse psyllium in water or aqueous solutions even with vigorous agitation... 

The determination of endogenous compounds and drugs in biological matrices has always presented a formidable challenge as one has to consider various factors before attempting to develop a suitable HPLC assay. These include the physicochemical properties of the compound such as the pKa value, solubility, volatility, particular functional groups (e.g., possessing chromophores, fluorophores, or electroactive characteristics), potential metabolites, and the required sensitivity and specificity. All these aspects will determine the type of extraction processes, analytical column selection, and suitable detector systems to be used as part of the HPLC apparatus. 

In the study by Parrott et al. [7], a generic PBPK model was applied to predict plasma profiles after intravenous and oral dosing to the rat for a set of 68 compounds from six different chemical classes. The compounds were selected without particular bias and so are considered representative of current Roche discovery compounds. The physicochemical properties of the compounds are rather different from those of marketed compounds in particular they have higher lipophilicity (mean logP = 4) and lower aqueous solubility as well as a tendency to be neutral at physiological pH. The more extreme property values can present experimental determination challenges and so for consistency all predictions were made on the basis of calculated lipophilicity and protein binding while in vitro... 

To date, the challenges associated with development of an oral MR dosage form for water-insoluble drugs have not been systematically studied and discussed. In many cases, the physicochemical properties of the drug and its sensitivity to the conditions of the Gl track make it more difL cult to attain the desired absorption and PK proLle. This is a clear point of concern in developing a MR product for poorly water-soluble drugs. 

The metabolome refers to the entire collection of metabolites, including lipids, sugars, amino acids, and nucleosides within an organism [2]. Though there is still some debate as to the exact number of metabolites, the current estimate is 6,800 human metabolites [25]. Compared to large biopolymers consisting of thousands of atoms, such as proteins and nucleic acids, the structures of many metabolites seem simple. However, this simplicity masks the unique challenge associated with analysis of the metabolome due to the distinct physicochemical properties of different classes of metabolites. For example, the isolation and analysis protocols... 

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