The use of structural alerts to avoid the toxicity of pharmaceuticals

Abstract

In order to identify compounds with potential toxicity problems, particular attention is paid to structural alerts, which are high chemical reactivity molecular fragments or fragments that can be transformed via bioactivation by human enzymes into fragments with high chemical reactivity. The concept has been introduced in order to reduce the likelihood that future candidate substances as pharmaceuticals will have undesirable toxic effects. A significant proportion (∼78-86%) of drugs characterized by residual toxicity contain structural alerts; there is also evidence indicating the formation of active metabolites as a causal factor for the toxicity of 62-69% of these molecules. On the other hand, the pharmacological action of certain drugs depends on the formation of reactive metabolites. Detailed assessment of the potential for the formation of active metabolites is recommended to characterize a biologically active compound. Although many prescribed drugs frequently contain structural alerts and form reactive metabolites, the vast majority of these drugs are administered in low daily doses. Avoiding structural alerts has become almost a norm in new drug design. An in-depth review of the biochemical reactivity of these structural alerts for new drug candidates is critical from a safety point of view and is currently being monitored in the discovery of drugs. The chemical strategies applied to structural alerts in molecules to limit the toxicity are: •partial replacement or full replacement of the structural alert;•reduction of electronic density;•introduction of a structural element of metabolic interest (metabolic switching);•multiple approaches. Therefore, chemical intervention strategies to eliminate bioactivation are often interactive processes; their success depends largely on a close working relationship between drug chemists, pharmacologists and researchers in metabolic science.

Keywords: Active metabolites; Structural alerts; Toxicity.

Fig. 1

Structures of raloxifene and its metabolites.

Fig. 2

Structures of procainamide and its metabolites.

Fig. 3

Structure of flecainide.

Fig. 4

Structures of carbutamide and tolbutamide.

Fig. 5

Structures of clozapine and its metabolites.

Fig. 6

Structures of loxapine and quetiapine.

Fig. 7

Structures of amodiaquine and its quinoneimine metabolite.

Fig. 8

Structures of nefazodone and its metabolites.

Fig. 9

Structure of vilazodone.

Fig. 10

Structures of practolol and atenolol.

Fig. 11

Structures of practolol desacetylation and oxidation productions.

Fig. 12

Structures of flunitrazepam and bromazepam.

Fig. 13

Structures of prasozin metbolites.

Fig. 14

Structures of prasozin and dexazosin.

Fig. 15

Structures of halothane, isoflurane and desflurane.

Fig. 16

Structures of halothane, trifluoroacetyl chloride and trigluoroacetylated proteins.

Fig. 17

Structures of ibufenac and ibuprofene.

Fig. 18

Structures of products of ibufenac bioactivation.

Fig. 19

Structures of imipramine and clomipramine.

Fig. 20

Structures of nifedipine & amlodipine.

Fig. 21

Structures of tolcapone and entacapone.

Fig. 22

Structure of zolpidem.

Fig. 23

Structures of alpidem and its metabolites.

Fig. 24

Structures of ticlopidine and its metabolites.

Fig. 25

Structures of clopidogrel and its metabolites.

Fig. 26

Structures of sudoxicam and 4-hydroxy-2-methyl-N-(2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide.

Fig. 27

Structures of sudoxicam, piroxicam and meloxicam.

Fig. 28

Structures of meloxicam and 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide.

Fig. 29

Structures of histamine, burimamide, and metiamide.

Fig. 30

Structures of cimetidine and ranitidine.