Metabolism drug-likeness

Cytochrome P450 2C19 Deficient activity in about 3% of Caucasian populations and in about 20% of Asian populations. Prolonged action of several CYP2C19 inactivated drugs like omeprazole or diazepam in the poor metabolizers. 

Singh SB, Shen LQ, Walker MJ, Sheridan RP. A model for likely sites of CYP3A4-mediated metabolism on drug-like molecules. J Med Chem 2003 46 1330-6. 

Molecular structure has been shown to influence absorption. By examining the structural characteristics of drugs that were in use, certain common characteristics of well-absorbed molecules were identified, commonly referred to as the rule of five. Some investigators have used this as a basis for characterizing the drug-likeness of a lead chemical. Other factors also come into play including receptor activity, metabolism profile and for CNS-active compounds, an ability to cross the blood-brain barrier. 

The generic term of drug-likeness implies a number of other properties [24] such as aqueous solubility, metabolism, blood-brain barrier penetration and oral absorption which are covered by other chapters in this book. 

When assayed in HEK293 cells transfected with the cloned human, rat and guinea pig TRPVl, (23a) showed similar potencies. Not unexpeetedly, (23a) showed poor metabolic stability and a structure-activity study to optimize potency and drug-like properties was initiated. Modification on the left-handed A -aryl section showed that ... 

This book is written for the practicing pharmaceutical scientist involved in absorption-distribution-metabolism-excretion (ADME) measurements who needs to communicate with medicinal chemists persuasively, so that newly synthesized molecules will be more drug-like. ADME is all about a day in the life of a drug molecule (absorption, distribution, metabolism, and excretion). Specifically, this book attempts to describe the state of the art in measurement of ionization constants (p Ka), oil-water partition coefficients (log PI log D), solubility, and permeability (artificial phospholipid membrane barriers). Permeability is covered in considerable detail, based on a newly developed methodology known as parallel artificial membrane permeability assay (PAMPA). 

The aim of the present example was to investigate whether the assessment of an in silico model of metabolic stability from a training set of several hundred drugs or drug-like compounds in human CYP3A4 cDNA-expressed microsomal preparations, would offer a suitable approach to predict the metabolic stability of external compounds. 

The genesis of in silico oral bioavailability predictions can be traced back to Lip-inski s Rule of Five and others qualitative attempts to describe drug-like molecules [13-15]. These processes are useful primarily as a qualitative tool in the early stage library design and in the candidate selection. Despite its large number of falsepositive results, Lipinski s Rule of Five has come into wide use as a qualitative tool to help the chemist design bioavailable compounds. It was concluded that compounds are most likely to have poor absorption when the molecular weight is >500, the calculated octan-l-ol/water partition coefficient (c log P) is >5, the number of H-bond donors is >5, and the number of H-bond acceptors is >10. Computation of these properties is now available as an ADME (absorption, distribution, metabolism, excretion) screen in commercial software such as Tsar (from Accelrys). The rule-of-5 should be seen as a qualitative, rather than quantitative, predictor of absorption and permeability [16, 17]. 

The incorporation of fluorine into a molecule has been widely used to alter the pharmacokinetic properties and overall drug-like properties of compounds. This includes affecting the metabolism, oral absorption, and brain penetration of these molecules [18]. Metabolism can be affected by addition of fluorine directly at or adjacent to the site of metabolism. In addition, substitution with fluorine can increase the lipophilicity of compounds which has been shown to dramatically affect both oral absorption and brain penetration. Finally, the electron-withdrawing characteristic of fluorine has been exploited to lower the P-gp liability of compounds and modulate the pKa of adjacent groups which resulted in increased brain exposure. In the following section, representative examples will highlight the powerful nature of fluorine to modulate overall drug-like properties. 

The contribution of pseudocholinesterase, also known simply as cholinesterase, to drug metabolism is much greater as it possesses considerably broader substrate selectivity. In addition to acetylcholine, it will hydrolyze other choline esters like the muscle relaxant succinylcholine. It will also hydrolyze non-choline-containing drugs like the local anesthetic procaine and the anti-inflammatory agent aspirin (Fig. 6.5). Cholinesterases, particularly... 

In vitro techniques for studying DDI potential are based on the metabolism of known marker substrates. Two assay types are typically used to study DDIs the turnover of drug-like probes monitored by LC-MS/MS methods or the use of spectrophotometer (plate reader) based methods. As each technique has unique advantages and shortcomings, assay use has not been standardized across the industry. Although techniques based on the turnover of radiolabeled substrates have also been developed [94—97], these methods are used infrequently and will not be discussed further. 

The methodology is very fast and completely automated. To predict the site of metabolism for drug-like substrates, the method requires few seconds per molecule. It is important to point out that the method uses neither any training set nor any statistical model or supervised technique, and it has proven to be predictive for extensively diverse validation sets preformed in different pharmaceutical companies. 

Inspite of all the qualified successes of synthetic drug research achieved in the last four decades to combat infectious diseases of the more than 80,000 different ailments, unfortunately only about one third can be treated with drugs, most of them only symptomatically. The discovery of better, effective and safer drugs is needed to fight the causes of dreadful diseases like cancer, acquired-immuno-deficiency-syndrome (AIDS), arthritis, cardio-vascular diseases, disorders of the central nervous system (CNS), such as Alzheimer s disease and other vital infectious and metabolic diseases like rheumatoid arthritis. 

Other drugs, like GHB and Rohypnol , can interact directly with the neurotransmitter receptors to either enhance or block the effects of the brain s own neurotransmitters. Still other drugs can alter the metabolic breakdown or clearance of certain neurotransmitters after they are released from the synaptic terminal, thereby altering how long the neurotransmitter affects the activity of other nearby neurons. 

Finally, a laboratory evaluation completes the initial evaluation. This includes a battery of blood tests to rule out infection, metabolic abnormality, or hormonal disturbance. It must also include a drug screen. Unfortunately, most drug screens do not detect the designer drugs like Ecstasy that are an ever-increasing cause of acute psychosis. The initial evaluation should always include a CT or MRI brain scan, preferably the latter. 

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