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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.
Download (direct link): pharmacokinetiksmedicanalchemistri2001.pdf
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Recently thalidomide and some of its metabolites (Figure 8.1) and related analogues have been shown to be inhibitors [2] of hFGF- and VEGF-induced neovascularization (angiogenesis). Such a finding readily provides an hypothesis for the causes of teratogenicity associated with thalidomide, since limb development (the site of teratogenesis) is dependent on the formation of new blood vessels.
A problem with toxicity produced by an extension of the pharmacology of a compound, is that the conventional use of no-effect doses based on pre-clinical animal studies may not apply. Moreover pre-clinical studies may be complicated by the often understated ranges of response seen across species due to species differences in the receptors, enzymes and ion channels that comprise drug targets. Table 8.1 lists some of these known variations and the consequences range from an exaggerated response, to an absence of a response.
H
Thalidomide
EM-12
Fig. 8Л Structures of thalidomide, EM-12 and their metabolites
8.1 Toxicity Findings 1101 Tab. 8.1 Receptors, ion channels and enzymes which are drug targets
and show species differences.
Receptors
Adenosine A1, A2 Luteinizing hormone lh
Adrenoceptors a1B" аю a2A Muscarinic M2
Atrial nutriuretic factor ANF-R1 Neurokinin K £ K1 N
Bradykinin B2 Purinoceptors P2
Cholecystokinin CCK Thromboxane TA2
Dopamine D1 Vanilloid
Endothelin ETb Vasopressin V1
Serotonin 5-HT1A, b, d 5-HT2, 5-HT3, 5-HT4
Ion Channels
Rapidly activating delayed
rectifier K+ channel
Enzymes
Carboxypeptidase B Renin
Na+/K+ ATPase HMG-CoA
reductase

8.1.2
Structure-related Toxicity
Findings related to the structure of the compound but not related to the pharmacology can provide another possible source of toxicity. This category is distinguished by the adverse events or effects being triggered by structural features or physicochemical properties etc. which allow the compound or metabolites to interact at sites distinct from the intended target or related proteins, etc. This type of toxicity can occur at any dose level including the therapeutic dose.
Amiodarone (Figure 8.2) is an efficacious drug that causes a number of side-ef-fects. The presence of iodine in the molecule is unusual and hypo- and hyperthyroidism have been reported in patients. Although the loss of iodine is relatively slow the relatively large daily dose size and long half-life of the drug and its de-ethylated metabolite suggest that the presence of iodine in the molecule is responsible for its toxicity [3].
102 | 8 Toxicity
The drug is also a highly lipophilic base and accumulates in a number of tissues including the lung. This combination of extreme physicochemical properties can result in more specific interactions such as the condition of phospholipidosis (increase in total lung phospholipids) caused by inhibition of phospholipid breakdown [4]. The medicinal chemist has to decide if extreme lipophilicity and the presence of iodine are essential for activity and, in the case of amiodarone, proven clinical efficacy or whether alternative structures are possible.
Proxicromil and FPL 52757 [5] were oral anti-allergy agents that utilized the strongly acidic “chromone” skeleton as a starting point (Figure 8.3). This skeleton contained the pharmacophore. To achieve oral absorption substantial lipophilicity was added and these changes resulted in surface active (detergent) molecules. The hepatobiliary route of excretion and resultant high concentrations of the compounds at the biliary cannaliculus resulted in hepatotoxicity [5].
8.1.3
Metabolism-induced Toxicity
Metabolism-induced toxicity results when a key function or grouping is altered by oxidation, reduction or conjugation to become reactive, normally an electrophile [6]. The electrophilic group is then capable of reacting with nucleophiles in the body. Nucleophilic functions are present in proteins, nucleic acids and small peptides such as glutathione (see Section 8.1.2). Reactions with these targets can lead to organ toxicity including carcinogenesis or simply excretion from the body (glutathione conjugates). Some indication of the possible targets [7] is indicated by the nature of the electrophile produced (soft-hard), as indicated in Figure 8.4.
Compounds that react with amino acids or proteins can trigger toxicity by two mechanisms. The direct mechanism involves reaction with specific proteins thus altering their function such that cell death and necrosis occurs. Such toxicities are often seen in a large number of subjects and are dose related. They are also often predicted from animal studies. Alternative mechanisms of toxicity involve an immune component, whereby the protein-metabolite conjugate triggers an immune response. Such toxicity is termed idiosyncratic, occurring in only a subset of the patients receiving the drug. This type of toxicity is not predicted normally by animal studies. These two types of toxicity are illustrated in the schematic shown in Figure 8.5. Glutathione and the glutathione transferase enzymes protect the body from
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