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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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for attack at allylic and benzylic positions pioglitazone; I, progesterone; J, testosterone;
(major sites of metabolism indicated by K, budesonide and L, salmeterol. asterisks). Substrates are A, cyclosporin A; B,
study of the soluble bacterial P450BM-3. In this case the substrates are fatty acids, which in aqueous solution adopt a “globular” conformation. However, upon entering the lipophilic access channel, the fatty acid opens out in an extended conformation with the lipophilic head group directed at the haem and the polar acid function directed at the solvent.
The enzyme is the principal participant in N-demethylation reactions where the substrate is a tertiary amine. The list of substrates includes erythromycin, ethylmor-phine, lidocaine, diltiazem, tamoxifen, toremifene, verapamil, cocaine, amiodarone, alfentanil and terfenadine. Carbon atoms in the allylic and benzylic positions, such as those present in quinidine, steroids and cyclosporin A, are also particularly prone to oxidation by CYP3A4, a range of substrates is illustrated in Figure 7.10.
Both these routes of metabolism reflect the ease of hydrogen or electron abstraction from these functions. As with conventional radical chemistry, reactivity needs to be combined with probability. Thus, in molecules such as terfenadine the tertiary butyl group will be liable to oxidation due to its “maximum number” of equivalent primary carbons. Thus, although not a specially labile function, the site of metabolism becomes dominated by statistical probability. Terfenadine, as expected, also undergoes N-dealkylation by CYP3A4, illustrating the ability of the enzyme to produce multiple products (as for cyclosporin A, midazolam, etc.) and underlining the “flexibility” of CYP3A4 substrate binding.
7.2 Cytochrome P450 | 83
Overcoming metabolism by CYP3A4 is difficult due to the extreme range of substrates and the tolerance of the enzyme to variations in structure. Two strategies are available: removal of functionality and reduction of lipophilicity.
Allylic and benzylic positions are points of metabolic vulnerability. SCH48461 is a potent cholesterol absorption inhibitor [7]. Metabolic attack occurred at a number of positions including benzylic hydroxylation. Dugar and co-workers substituted oxygen for the C-3' carbon to remove this site of metabolism. This step however, produces an electron-rich phenoxy moiety in comparison to the original phenyl group and possibly makes this function more amenable to aromatic hydroxylation. Blocking of the aromatic oxidation with fluorine introduced in the para-position was required to produce the eventual more stable substitution. These steps are shown in Figure 7.11.
Fig. 7.11 Synthetic strategies to overcome benzylic hydroxylation in a series of cholesterol absorption inhibitors. Positions of metabolism are marked with an asterisk.
The lability of benzylic positions to cytochrome P450 metabolism has been exploited to decrease the unacceptably low clearance and resultant long half-life of various compounds. For example celecoxib, a selective cyclooxygenase inhibitor, has a half-life of 3.5 h in the rat. Early structural leads, represented by compounds in
Fig. 7.12 Structures of early long half-life COX2 inhibitor (A) and the candidate compound celecoxib (B) with a moderate half-life.
84 | 7 Metabolic (Hepatic) Clearance
which the benzylic methyl in celecoxib was substituted with a halogen (Figure 7.12), resulted in compounds with half-life values (in the male rat) of up to 220 h [8].
Diltiazem (Figure 7.13), a calcium channel blocker, is a drug that is extensively metabolized by at least five distinct pathways including N-demethylation, deacetyla-tion, O-demethylation, ring hydroxylation and acid formation. The enzyme responsible for at least the major route (N-demethylation), has been shown to be CYP3A4 [8]. Although widely used in therapy, the compound has a relatively short duration of action. In the search for superior compounds, Floyd et al. [9] substituted the ben-zazepinone ring structure for the benzothiazepinone of diltiazem. Metabolic studies on this class of compound showed that the principal routes of metabolism were similar to that for diltiazem with N-demethylation, conversion to an aldehyde (precursor of an acid), deacetylation and O-demethylation all occurring. It was also noted that the N-desmethyl derivative was equipotent to the parent but much more stable meta-bolically. This can be rationalized as the decreased substitution on the nitrogen (secondary versus tertiary) stabilizing the nitrogen to electron abstraction (decreased radical stability). This stabilization is particularly important, since electron abstraction is the first step to both the N-desmethyl and aldehyde products (a total of 84 % of the total metabolism). The evidence of stability of secondary amines was capitalized on by synthesis of N-1 pyrrolidinyl derivatives, which were designed to achieve metabolic stability both by the decreased radical stability of secondary compounds to tertiary amines and steric hindrance afforded by p-substitution (Figure 7.11). The success of this strategy indicates how even the vulnerable alkyl substituted nitrogen grouping can be stabilized against attack.
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