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Organic Medicinal Chemistry
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Organic Medicinal Chemistry
The practice of medicinal chemistry devoted to the discovery and development of new drugs.
Metabolism
The biotransformation of drugs in the body. Important in the elimination of drugs from the body. Converts drugs to hydrophilic, inactive, and nontoxic forms.
Liver
The primary organ involved in drug metabolism. It performs metabolic functions in two phases: functionalization and conjugation.
Phase I Functionalization
The introduction of a polar functional group (e.g., OH, COOH, NH2, SH) by direct introduction or modifying/unmasking existing functionalities. It produces a handle on the molecule for Phase II reactions such as oxidation, reduction, and hydrolysis.
Oxidation
The most common phase I reaction involving the conversion of olefins, alcohols, aldehydes, and aromatic moieties (e.g., phenylbutazone) to hydrophilic and inactive metabolites (e.g., oxybutazone).
Reduction
Involves the conversion of compounds to inactive forms through reduction reactions. This includes drugs like Prednisone and other primary amino groups.
Hydrolysis
A process commonly undergone by lactams, esters, and amides, leading to the formation of hydrophilic and inactive metabolites.
Phase II Conjugation
The attachment of small ionizable endogenous compounds to the functional handles produced in Phase I. This includes reactions such as glucuronidation, sulfation, glycine/glutamine conjugation, glutathione, acetylation, and methylation.
Glucuronidation
A phase II conjugation reaction involving the transferase enzyme (TE) Glucuronyltransferase, which attaches D-glucuronic acid to functional groups. This process forms excretable inactive metabolites and terminates/attenuates drug activity.
Sulfation
A phase II conjugation reaction involving the transferase enzyme (TE) Sulfotransferase, leading to the formation of water-soluble and inactive conjugates of endogenous compounds such as steroids, heparin, catecholamines, and thyroxine.
Glycine/Glutamine Conjugation
A phase II conjugation reaction that involves the conjugation of carboxylic acids, particularly aromatic acids and arylalkyl acids, with glycine in mammals and glutamine in humans and primates.
Glutathione
A phase II conjugation reaction used for detoxifying chemically reactive electrophilic compounds. It is composed of three amino acids (cysteine, glycine, and glutamine) and is responsible for detoxification.
Acetylation
A phase II conjugation reaction used for the termination of drug activity and detoxification, particularly of primary amino groups. It involves the transferase enzyme (TE) N-acetyltransferase and is undergone by compounds like sulfonamides.
Methylation
A phase II conjugation reaction involving the transferase enzyme (TE) Methyltransferase, leading to the biosynthesis of non-polar and inactivated compounds. It is important in the biosynthesis of epinephrine, melatonin, and inactivating compounds.
First Pass Metabolism
Pre-systemic metabolism, where orally administered drugs are extensively metabolized before reaching the systemic circulation. This process is particularly relevant for drugs with extensive first-pass metabolism like propranolol, isosorbide dinitrate, and lidocaine.
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What is the practice of medicinal chemistry devoted to?
The discovery and development of new drugs
What is metabolism in the context of organic medicinal chemistry?
The biotransformation of drugs in the body, important in the elimination of drugs from the body
What are the two phases of metabolism in the context of organic medicinal chemistry?
Functionalization and Conjugation
What is Phase I Functionalization and what are the types of reactions involved?
It introduces a polar functional group by direct introduction or modifies/unmasks existing functionalities. Reactions involved are oxidation, reduction, and hydrolysis.
What is the most common phase I reaction and what compounds undergo it?
Oxidation, undergone by olefins, alcohols, aldehydes, aromatic moieties (e.g., Phenylbutazone to oxybutazone)
What compounds commonly undergo hydrolysis in Phase I Functionalization?
Lactams, esters, and amides
What is Phase II Conjugation and what are the reactions involved?
It attaches small ionizable endogenous compounds to the functional handles. Reactions involved are glucuronidation, sulfation, glycine glutamine conjugation, glutathione, acetylation, and methylation.
What are the purposes of Phase II Conjugation?
1. Form excretable inactive metabolites 2. Terminate/Attenuate activity 3. Detoxify
What is Glucuronidation and what coenzyme and enzyme are involved?
It involves the transferase enzyme and the coenzyme Uridine diphospho D-glucuronic acid (UDPGA) and glucuronyltransferase. It is the most common conjugation reaction.
What is Sulfation and what coenzyme and enzyme are involved?
It involves the coenzyme 3-phosphoadenosine 5-phosphosulfate (PAPS) and sulfotransferase. It yields water-soluble and inactive conjugates.
What is Glycine Glutamine Conjugation and what compounds does it commonly involve?
It involves conjugating carboxylic acids, particularly aromatic acids and arylalkyl acids. Glycine is common to mammals, while glutamine is found in humans and other primates.
What is Glutathione used for in Phase II Conjugation?
It is used for detoxifying chemically reactive electrophilic compounds. Glutathione is composed of 3 amino acids: cysteine, glycine, and glutamine.
What is the purpose of Acetylation in Phase II Conjugation and what is the important route for this process?
It is for the termination of activity and detoxification. The important route is the acetylation polymorphism, with variation in acetylating activity.
What is Methylation and what coenzyme and enzyme are involved?
It is a minor pathway that leads to nonpolar inactivated compounds and involves the coenzyme S-Adenosylmethionine (SAM) and methyl transferase.
What is first pass metabolism?
It is pre-systemic metabolism where orally administered drugs are extensively metabolized before reaching the systemic circulation.
Scholarly Assistant's Insights
An overview of Organic Medicinal Chemistry, drug metabolism, the liver's role, and drug transformations in the body.
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