Preclinical drug development

Pharmacology and medicinal chemistry have transformed medicine from an intellectual exercise in diagnosis into a powerful force for the relief of human disease (CT DoHerv 1994)'

The development of new medicines (drugs) is an exercise in prediction from laboratory studies in vitro and in vivo (animals), which forecast what the agent will do to man. Medicinal therapeutics rests on the two great supporting pillars of pharmacology:

• Selectivity: the desired effect alone is obtained; 'We must learn to aim, learn to aim with chemical substances' (Paul Ehrlich).2

• Dose:'.. .The dose alone decides that something is no poison' (Paracelsus).3

For decades the rational discovery of new medicines has depended on modifications of the molecular structures of increasing numbers of known natural chemical mediators. Often the exact molecular basis of drug action is unknown, and this book contains frequent examples of old drugs whose

1 In this chapter we are grateful for permission from Professor Sir Colin Dollery to quote directly and indirectly from his Harveian Oration, 'Medicine and the pharmacological revolution' (1994) Journal of the Royal College of Physicians of London 28: 59-69.

2 Paul Ehrlich (1845-1915), German scientist who pioneered the scientific approach to drug discovery. The 606"' organic arsenical that he tested against spirochaetes (in animals) became a successful medicine (Salvarsan 1910); it and a minor variant were used against syphillis until superseded by penicillin in 1945.

3 Paracelsus (1493-1541) was a controversial figure who has been portrayed as both ignorant and superstitious. He had no medical degree; he burned the classical medical works (Galen, Avicenna) before his lectures in Basel (Switzerland) and had to leave the city following a dispute about fees with a prominent churchman. He died in Salzburg (Austria) either as a result of a drunken debauch or because he was thrown down a steep incline by 'hitmen' employed by jealous local physicans. But he was right about the dose.

mechanism of action remains mysterious. The evolution of molecular medicine (including recombinant DNA technology) in the past 20 years has led to a new pathway of drug discovery: pharmacogenomics.4 This broad term encompasses all genes in the genome that may determine drug response, desired and undesired. Completion of the Human Genome Project in 2001 has yielded a minimum of 30 000 potential drug targets, although the function of many of these genes remains unknown. In the future, drugs may be designed according to individual genotypes, thereby to enhance safey as well as efficacy.

The chances of discovering a truly novel medicine, i.e. one that does something valuable that had previously not been possible (or that does safely what could only previously have been achieved with substantial risk), are increased when the development programme is founded on precise knowledge, at molecular level, of the biological processes it is desired to change. The commercial rewards of a successful product are potentially enormous and provide a massive incentive to developers to invest and risk huge sums of money.

Studies of signal transduction, the fundamental process by which cells talk to one another as intracellular proteins transmit signals from the surface of the cell to the nucleus inside, have opened an entirely new approach to the development of therapeutic agents that can target discrete steps in the body's elaborate pathways of chemical reactions. The opportunities are endless.5

The molecular approach to drug discovery should enable a 'molecular dissection' of any disease process. There are two immediate consequences:

• More potential drugs and therapeutic targets will be produced than can be experimentally validated in animals and man. A further risk is that this 'production line' approach could lead to a loss of integration of the established specialities

4An example of the opportunity created by pharmacogenomics comes in the announcement by a major pharmaceutical company of plans to search the entire human genome for genetic evidence of intolerance to one of its drugs. If achieved, adverse reactions to the drug would be virtually eliminated.

5Culliton B J 1994 Nature Medicine 1:1

(chemistry, biochemistry, pharmacology), and an overall lack of understanding of how physiological and pathophysiological processes contribute to the interaction of drug and disease.

• New drugs could be targeted at selected groups of patients based on their genetic make-up.

This concept of 'the right medicine for the right patient' is the basis of pharmacogenetics (see p. 122), the genetically determined variability in drug response. Pharmacogenetics has gained momentum from recent advances in molecular genetics and genome sequencing, due to:

• Rapid screening for specific gene polymorphisms (see p. 122).

• Knowledge of the genetic sequences of target genes such as those coding for enzymes, ion channels, and other receptor types involved in drug response.

The expectations of pharmacogenetics and its progeny, pharmacoproteomics (understanding of and drug effects on protein variants), are high. They include:

• Identification of subgroups of patients with a disease or syndrome based on their genotype.

• Targeting specific drugs for patients with specific gene variants.

Consequences of these expectations include: smaller clinical trial programmes, better understanding of the pharmacokinetics and dynamics according to genetic variation, simplified monitoring of adverse events after marketing. A great challenge will be to determine the function of each polymorphic gene (or gene product) and whether it has pharmacological or toxicological importance. Some of the expectations for both pharmacogenomics and pharmacogenetics have been exaggerated: at the least, the timescale over which the expectations may be realised is longer than first thought.

Nevertheless, exploitation of the new technologies will create more potential medicines, and more doctors will become involved in clinical testing; it is expedient that they should have some acquaintance with the events and processes that precede their involvement.

Sources of compounds

Therapeutic targets

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