Introduction or removal of a ring system

The introduction of a ring system changes the shape and increases the overall size of the analogue. The effect of these changes on the potency and activity of the analogue is not generally predictable. However, the increase in size can be useful in filling a hydrophobic pocket in a target site, which might strengthen the binding of the drug to the target. For example, it has been postulated that the increased inhibitory activity of the cyclopentyl analogue (rolipram) of...

Leads and analogues some desirable properties 141 Bioavailability

The activity of a drug is related to its bioavailability, which is defined as the fraction of the dose of a drug that is found in general circulation (see section 11.5). Consequently, for a compound to be suitable as a lead it must be bioavailable. In order to assess a compound's bioavailability it must be either available off the shelf or be synthesised. Synthesis of a compound could result in the synthesis of an inactive compound, which could be expensive both in time and money. In order to...

Dialysis

Dialysis is used to separate small (< 1000 Da) from larger molecules in aqueous solution. Small molecules will pass through the pores in a semipermeable membrane when a concentration gradient exists across that membrane. In small-scale operations the sample is placed in a semipermeable membrane bag and suspended in pure water. Small molecules will diffuse through the membrane into the pure water until their concentration inside the bag equals their concentration outside the bag. Replacing the...

Questions

1 Predict, giving a reason for the prediction, the most likely general effect of the stated structural change on either the in situ stability or the pharmacological action of the stated drug. (a) The introduction of ortho ethyl groups in dimethylaminoethyl 4-aminobenzoate. (b) The replacement of the amino group in the CNS stimulant amphetamine (PhCH2CH(NH2)CH3) by a trimethylammonium chloride group. (c) The replacement of the ester group in the local anaesthetic ethyl 4-aminobenzoate...

An example of the use of overlays

DuPont carried out a SAR study in the early 1980s using N-benzylimidazole-5-ethanoic acids (Fig. 4.12a) that had been shown to be weak angiotensin II antagonists (see section 9.12.2). It resulted in the discovery of the highly active antihypertensive drug Losartan. This stimulated research based on a 2'-tetrazolyl-biphenyl template. At the same time Eli-Lilly carried out a SAR investigation to discover new angiotensin II antagonists based on N-imidazole-2-octanoic acid (Fig. 4.12b). It was...

Methods and routes of administration the pharmaceutical phase

The form in which a medicine is administered is known as its dosage form. Dosage forms can be subdivided according to their physical nature into liquid, semisolid and solid formulations. Liquid formulations include solutions, suspensions, and emulsions. Creams, ointments and gels are normally regarded as semisolid formulations, whilst tablets, capsules and moulded products such as suppositories and pessaries are classified as solid formulations. These dosage forms normally consist of the active...

Classification of drugs

Drugs are classified in different ways depending on where and how the drugs are being used. The methods of interest to medicinal chemists are chemical structure and pharmacological action, which includes the site of action and target system. However, it is emphasised that other classifications, such as the nature of the illness, are used both in medicinal chemistry and other fields depending on what use is to be made of the information. In all cases, it is important to bear in mind that most...

Drug discovery and design a historical outline

Since ancient times the peoples of the world have had a wide range of natural products that they use for medicinal purposes. These products, obtained from animal, vegetable and mineral sources, were sometimes very effective. However, many of the products were very toxic and it is interesting to note that the Greeks used the same word pharmakon for both poisons and medicinal products. Information about these ancient remedies was not readily available to users until the invention of the printing...

Changing the degree of unsaturation

The removal of double bonds increases the degree of flexibility of the molecule, which may make it easier for the analogue to fit into active and receptor sites by taking up a more suitable conformation. However, an increase in flexibility could also result in a change orloss of activity. The introduction of a double bond increases the rigidity of the structure. It may also introduce the complication of E and Z isomers, which could have quite different activities (see Table 1.1). The analogues...

Abbreviations

ACE Angiotensin-converting enzymes ADAPT Antibody-directed abzyme prodrug therapy ADEPT Antibody-directed enzyme prodrug therapy ADME Absorption, distribution, metabolism and elimination AIDS Acquired immuno deficiency syndrome BESOD Bovine erythrocyte superoxide dismutase cAMP Cyclic adenosine monophosphate CoMFA Comparative molecular field analysis CYP-450 Cytochrome P-450 family dATP Deoxyadenosine triphosphate DMPK Drug metabolism and pharmacokinetics EDRF Endothelium-derived relaxing...

Jl

(1) (CH3)3Si 2N2 N y-N (2) PhCOOCH2CH2OCH2Cl N' -T i -uu (C2H5),N ,, . .i- -- Figure 2.12 Examples of the methods of introducing polyhydroxy and ether groups into a lead structure Glucosamine 95 ethanol heat 2-3 hours Isonicotinic acid hydrazide (antituberculostatic) HO OH Glucametacin (anti-inflammatory) Figure 2.13 Examples of the use of sugar residues to increase water solubilities of drugs

Sources of leads and drugs

Chemical Constituent Foxgloves Leaf

Originally drugs and leads were derived from natural sources. These natural sources are still important sources of lead compounds and new drugs, however the majority of lead compounds are now discovered in the laboratory using a variety of sources, such as local folk remedies (ethnopharmacology), investigations into the biochemistry of the pathology of disease states and high-throughput screening of compound collections (see Chapter 5), databases and other literature sources of organic...

Case history the story of Taxol

The story of the discovery of Taxol (paclitaxel) is a good example of the time and persistence required to extract a new drug or lead from natural material. It also illustrates some of the difficulties encountered in this process and the multidisciplinary nature of the process. The story starts with a plant antitumour screening programme initiated by J. H. Hartwell of the American National Cancer Institute (NCI) in 1960. In 1962, 650 extracts were investigated by laboratories under contract to...

Changing the existing substituents of a lead

Analogues can also be formed by replacing an existing substituent in the structure of a lead by a new substituent group. The choice of group will depend on the objectives of the design team. It is often made using the concept of isosteres. Isosteres are groups that exhibit some similarities in their chemical and or physical properties. As a result, they can exhibit similar pharmacokinetic and pharmacodynamic properties. In other words, the replacement of a substituent by its isostere is more...