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Methods and Principles in Medicinal Chemistry - Mannhold R.

Mannhold R., Kubinyi H., Timmerman H. Methods and Principles in Medicinal Chemistry - Wiley-VCH, 2001. - 155 p.
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1.0 ......—----------—--—---
1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5
log D at pH 7.4
Fig. I.7 1 so-molecular weight curves showing the influence of molecular size on membrane permeability with increasing lipophilicity [32].
1.6 Computational Approaches to Lipophilicity |9
lene glycol dipelargonate (PGDP) has been advocated [33-34]. By measuring distribution in all four, a full coverage of partitioning properties should be obtained. Also non-aqueous systems such as heptane/acetonitrile [35] or heptane/glycol [36] may be of use. This latter system appears to offer a direct measure for hydrogen bonding. In order to increase throughput over the traditional shake-flask and related methods, various chromatographic techniques can be used [1]. Immobilized artificial membranes (IAM) in particular, have been given considerable attention [37, 38]. IAMs consist of phospholipids grafted onto a solid phase HPLC support intended to mimic a membrane. It appears that IAM retention times are highly correlated with shake flask log D octanol/water coefficients and thus do not really measure anything new. Along the same lines several groups have suggested that studying partitioning into liposomes may produce relevant information related to membrane uptake and absorption [38, 39].
Fig. 1.8 Experimental methods to measure lipophilicity (modified after reference [23 ]). log Poct, 1 -octanol/water partition coefficient; log Pliposomes, partition coefficient between liposomes and buffer; log Phexane, 1-hexane/water partition coefficient; logPPGDP, propyleneglycol dipelargonate/water partition coefficient; log Pheptane/glycol» a non-aqueous partitioning system; SF, shake-flask; pH-metric, log P determination based on potentiometric titration in water and octanol/water; CPC, centrifugal partition chromatography; RP-HPLC, reversed-phase high performance liquid chromatography; TLC, thin-layer chromatography; ODS, octa-decylsilane; ABZ, end-capped silica RP-18 column; ODP, octade-cylpolyvinyl packing; IAM, immobilized artificial membrane;
ILC, immobilized liposome chromatography; MEKC, micellar electrokinetic capillary chromatography.
Computational Approaches to Lipophilicity
In the design of new compounds as well as the design of experimental procedures an a priori calculation log P or log D values may be very useful. Methods may be based on the summation of fragmental [40-42], or atomic contributions [43-45], or a combination [46, 47]. Reviews on various methods can be found in references [40, 48-51]. Further approaches based on the used of structural features have been suggested [48,
10 | 1 Physicochemistry
52]. Atomic and fragmental methods suffer from the problem that not all contributions may be parameterized. This leads to the observation that for a typical pharmaceutical file about 25 % of the compounds cannot be computed. Recent efforts have tried to improve the “missing value” problem [53].
Molecular lipophilicity potential (MLP) has been developed as a tool in 3D-QSAR, for the visualization of lipophilicity distribution on a molecular surface and as an additional field in CoMFA studies [49]. MLP can also be used to estimate conformation-dependent log P values.
Membrane Systems to Study Drug Behaviour
In order to overcome the limitations of octanol other solvent systems have been suggested. Rather than a simple organic solvent, actual membrane systems have also been utilized. For instance the distribution of molecules has been studied between unilamellar vesicles of dimyristoylphosphatidylcholine and aqueous buffers. These systems allow the interaction of molecules to be studied within the whole membrane which includes the charged polar head group area (hydrated) and the highly lipophilic carbon chain region. Such studies indicate that for amine compounds ionized at physiological pH, partitioning into the membrane is highly favoured and independent of the degree of ionization. This is believed to be due to electrostatic interactions with the charged phospholipid head group. This property is not shared
Fig. 1.9 Structures of charge neutral (phosphatidylcholine) and acidic (phosphatidylser-ine) phospholipids together with the moderately lipophilic and basic drug chlorphenter-mine. The groupings R1 and R2 refer to the acyl chains of the lipid portions.
1.7 Membrane Systems to Study Drug Behaviour 111
with acidic compounds even for the “electronically neutral” phosphatidylcholine [54]. Such ionic interactions between basic drugs are even more favoured for membranes containing “acidic” phospholipids such as phosphatidylserine [55]. The structures of these two phospholipids are shown in Figure 1.9 below together with the structure of the basic drug chlorphentermine.
Table 1.1 shows the preferential binding of chlorphentermine to phosphatidylcholine-containing membranes, the phospholipid with overall acidic charge. These systems predict the actual affinity of the compound for the membrane, rather than its ability to cross the membrane. Membrane affinity, and hence tissue affinity, is particularly important in the persistence of drugs within the body, a topic which will be covered in Section 4.2.
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