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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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Practolol (Figure 8.13) was the prototype cardioselective —Ä-adrenoceptor blocking agent. Selectivity was achieved by substitution in the para position with an acetyl anilino function. The similarity of this drug with those outlined above is obvious. Practolol caused severe skin and eye lesions in some patients which led to its withdrawal from the market [6]. These lesions manifested as a rash, hyperkeratosis, scarring, even perforation of the cornea and development of a fibrovascular mass in the conjunctiva, and sclerosing peritonitis. Some evidence is available that the drug is oxidatively metabolized to a reactive product that binds irreversibly to tissue pro-
8.3 Quinone Imines 107
Fig. 8.12 Metabolism of indomethacin to a reactive iminoquinone metabolite.
Fig. 8.13 Structures of
practolol and atenolol. practolol atenolol
teins. That the toxic functionality is the acetanilide is confirmed by the safety of a follow-on drug atenolol. Atenolol (Figure 8.13) has identical physicochemical properties and a very similar structure except that the acetyl-amino function has been replaced with an amide grouping. This structure cannot give rise to similar aromatic amine reactive metabolites. The withdrawal of practolol from the market is obviously a severe blow to the manufacturer and to those patients who benefited from it. Although not shown to be the cause of toxicity the presence of an aromatic amine in the structure of nomifensine (Figure 8.14) has to be treated with suspicion, the compound was also withdrawn from the market 9 years after its launch due to a rising incidence of acute immune haemolytic anaemia [15].
Carbutamide was the first oral anti-diabetic, and the prototype for the sul-phonamide type of agent. Carbutamide caused marked bone marrow toxicity in man, but derivatives of this, not containing the anilino function, such as tolbutamide
108 8 Toxicity
Fig. 8.15 Structures of carbutamide an oral anti-diabetic, associated with bone marrow toxicity, and tolbutamide a compound without similar effects.
(Figure 8.15), were devoid of such toxicity. As for many of the agents featured in this section the structural similarity between carbutamide and tolbutamide clearly implicates the anilino function as the toxicophore.
A –í
Fig. 8.16 Structures of Na+ channel blocker antiarrythmics: lidocaine (A), procaineamide (B), tocainide (C) and flecainide (D).
8.4 Nitrenium Ions 109
A further example of the design of drugs to remove aromatic amine functionalities even when present as a amide, is illustrated by the Na+ channel class of antiarrhyth-mic drugs [16]. Lidocaine is very rapidly metabolized (Figure 8.16) and so is only useful as a short-term intravenous agent. Oral forms include procainamide, tocainide and flecainide (Figure 8.16). Procainamide causes fatal bone marrow aplasis in 0.2 % of patients and lupus syndrome in 25-50 %. Tocainide also causes bone marrow aplasis and pulmonary fibrosis. In contrast, flecainide, whose structure contains no aromatic amine, masked or otherwise, has adverse effects related directly to its pharmacology. Interestingly, the lupus syndrome seen with procainamide is largely absent when N-acetyl procainamide is substituted.
Nitrenium Ions
Clozapine, an antipsychotic agent, has the potential to cause agranulocytosis with an incidence of 1 %. The major oxidant in human neutrophils, HOCl, oxidizes clozapine to a nitrenium ion (Figure 8.17) in which the positive charge is highly delocalized. This metabolite is capable of binding irreversibly to the neutrophil [17]. A variety of cells including liver, neutrophils and bone marrow can form reactive clozapine metabolites which react to form glutathione thioether adducts [18].
Fig. 8.17 Structures of clozapine and its nitrenium ion, the postulated reactive metabolite generated by oxidation.
Various analogues have been investigated indicating that the nitrogen-bridge between the two aromatic rings is the target, at least for HOCl oxidation. When alter-
110 | 8 Toxicity
native bridging heteroatoms are used (Figure 8.18) similar reactive metabolites are not observed [19].
8.5 Iminium Ions
Mianserin is a tetracyclic antidepressant that causes agranulocytosis in isolated cases in patients. Detailed structural analysis [20] has indicated that oxidation by cytochrome P450 to one or more iminium ions is the likely causative first step in this toxicity, the most likely being the C4-N5 version (Figure 8.19). Evidence for this is provided by the C14p methyl and the 010 analogues which cannot form the corresponding nitrenium and carbonium ions, but are cytotoxic. Removal of the N5 nitrogen atom in analogous structures abolishes production of the reactive metabolites (Figure 8.20).
Fig. 8.20 Structures of mianserin analogues. A and B cannot form the N5-C14b iminium and C10 carbonium ion but are still toxic. C without the N5 nitrogen is not toxic implicating the C4-N5 iminium ion.
8.6 Hydroxylamines 111
Vesnarinone is a drug used to treat congestive heart failure and is associated with a 1 % incidence of agranulocytosis. When metabolized by activated neutrophils the major metabolite is veratrylpiperazinamide (Figure 8.21). This unusual N-dealkyla-tion (of an aromatic ring) can be rationalized by chlorination of the nitrogen to which the aromatic ring is attached by HOCl, followed by the loss of HCl to form the reactive imminium ion, which itself can react with nucleophiles. Hydrolysis of the iminium ion yields veratrylpiperazinamide and another reactive species, the quinone imine (see Section 8.3).
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