山东大学：《药物化学 Medicinal Chemistry》课程教学资源（PPT课件讲稿）Chapter 13 New methods and techniques

Medicinal chemistry Chapter 13 New Methods and Techniques

Medicinal chemistry Chapter 13 New Methods and Techniques

Prodrug The term prodrug, which was used initially by Albert Hl, is a pharmacologically inactive compound that is converted into an active drug by a metabolic biotransformation a prodrug also can be activated by a nonenzymatic process such as hydrolysis but in this case the compounds generally are inherently unstable and may cause stability problems

Prodrug • The term prodrug, which was used initially by Albert HI, is a pharmacologically inactive compound that is converted into an active drug by a metabolic biotransformation. • A prodrug also can be activated by a nonenzymatic process such as hydrolysis, but in this case the compounds generally are inherently unstable and may cause stability problems

The prodrug to drug conversion can occur before absorption, during absorption, after absorption, or at a specific site in the body In the ideal case a prodrug is converted to the drug as soon as the desired goal for designing the prodrug has been achieved

• The prodrug to drug conversion can occur before absorption, during absorption, after absorption, or at a specific site in the body. • In the ideal case a prodrug is converted to the drug as soon as the desired goal for designing the prodrug has been achieved

Soft drug Soft drugs are biologically active drugs designed to have a predictable and controllable metabolism to nontoxic and inactive products after they have achieved their desired pharmacological ettect The molecule could be deactivated and detoxified shortly after it has exerted its biological effect, the therapeutic index could be increased, providing a safer drug

Soft Drug • Soft drugs are biologically active drugs designed to have a predictable and controllable metabolism to nontoxic and inactive products after they have achieved their desired pharmacological effect. • The molecule could be deactivated and detoxified shortly after it has exerted its biological effect, the therapeutic index could be increased, providing a safer drug

Feature It has a close structural similarity to the lead; It has a meta bolically sensitive moiety built into the lead structure The incorporated metabolically sensitive spot does not affect the overall physicochemical or steric properties of the lead compound

Feature • It has a close structural similarity to the lead; • It has a metabolically sensitive moiety built into the lead structure; • The incorporated metabolically sensitive spot does not affect the overall physicochemical or steric properties of the lead compound;

Advantages Elimination of toxic metabolites, thereby increasing the therapeutic index of the drug Avoidance of pharmacologically active metabolites that can lead to long-term effects; Elimination of drug interactions resulting from metabolite inhibition of enzymes Simplification of pharmacokinetic problems caused by multiple active species

Advantages • Elimination of toxic metabolites, thereby increasing the therapeutic index of the drug; • Avoidance of pharmacologically active metabolitesthat can lead to long-term effects; • Elimination of drug interactions resulting from metabolite inhibition of enzymes; • Simplification of pharmacokinetic problems caused by multiple active species

The difference between prodrugs and soft durgs The concepts of prodrugs and soft drugs are opposite, as follow a prodrugs is an inactive compound that requires a meta bolic conversion to the active form a soft drug is pharmacologically active and uses metabolism as a means of promoting excretion

The difference between prodrugs and soft durgs • The concepts of prodrugs and soft drugs are opposite, as follow: • A prodrugs is an inactive compound that requires a metabolic conversion to the active form; • A soft drug is pharmacologically active and uses metabolism as a means of promoting excretion

However, it is possible to design a pro-soft drug a modified soft drug that requires metabolic activation for conversion to the active soft drug

• However, it is possible to design a pro-soft drug, a modified soft drug that requires metabolic activation for conversion to the active soft drug

Hard drugs Hard drugs are nonmetabolizable compounds characterized either by high lipid solubility and accumulation in adipose tissues and organelles or high water solubility They are poor substrates for the metabolizing enzymes, the potentially metabolically sensitive parts of these drugs are either sterically hindered or the hydrogen atoms are substituted with halogens to block oxidation

Hard Drugs • Hard drugs are nonmetabolizable compounds, characterized either by high lipid solubility and accumulation in adipose tissues and organelles or high watersolubility. • They are poor substrates for the metabolizing enzymes; the potentially metabolically sensitive parts of these drugs are either sterically hindered or the hydrogen atoms are substituted with halogensto block oxidation

QSAR Quantitative structure-activity relationships (Qsar represent an attempt to correlate structural or property descriptors of compounds with activitⅰeS These physicochemical descriptors, which include parameters to account for hydrophobicity topology electronic properties, and steric effects, are determined empirically or, more recently by computational methods

QSAR • Quantitative structure-activity relationships (QSAR) represent an attempt to correlate structural or property descriptors of compounds with activities. • These physicochemical descriptors, which include parameters to account for hydrophobicity, topology, electronic properties, and steric effects, are determined empirically or, more recently, by computationalmethods