Oxidative Metabolism and Drug Design

In addition to the examples indicated above the design of orally-active cholesterol absorption inhibitors combines both the concept of preventing metabolism and the serendipity of metabolites being more active than the parent drug [10]. On the basis of metabolite structure-activity relationships for SCH 48461 (Figure 7.15), SCH 58335 was designed to combine activity-enhancing oxidation and to remove or block sites of detrimental metabolic oxidation. The improvement in the pharmacodynamics of the compound is illustrated by the ED50 being reduced in the cholesterol hamster model from 2.2 to 0.04 mg kg-1 day-1.

OMe OH

OMe OH

Fig. 7.15 Structures of cholesterol absorption inhibitors SCH 48461 (A) and SCH 58235 (B). Metabolism of SCH 48461 occurs by aromatic hydrox-ylation (1) benzylic hydroxylation (2) and O-demethylation (3, 4). Metabolism is blocked in SCH 58235 at 1 and 4 or results in increases in potency at 2 and 3.

Fig. 7.15 Structures of cholesterol absorption inhibitors SCH 48461 (A) and SCH 58235 (B). Metabolism of SCH 48461 occurs by aromatic hydrox-ylation (1) benzylic hydroxylation (2) and O-demethylation (3, 4). Metabolism is blocked in SCH 58235 at 1 and 4 or results in increases in potency at 2 and 3.

Fig. 7.16 Steps in the discovery of cromakalim: initial structure (A), more potent pyrrolidine analogue (B) and active metabolite (cromakalim C).

The discovery of the potassium channel opener cromakalim is another example of metabolism providing novel active molecules [11]. The programme was designed to find agents that were antihypertensive without having p-adrenoceptor blocking activity. This was due to the belief that p-adrenoceptor blockade was not solely responsible for the antihypertensive effects of p-adrenoceptor blockers. Early compounds were synthesized as cyclized derivatives of p-adrenoceptor blockers. The initial lead is illustrated in Figure 7.16. The gem-dimethyl group and an electron-withdrawing group on the aromatic ring were essential. Cyclic amino groups were preferred to the original isopropylamine, leading to the pyrrolidine derivative. The eventual candidate cromakalim was produced by investigating the metabolites of the pyrrolidine derivative, an oxidation to amines to produce amides being a common metabolic step in cyclic amide systems.

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