Designing safer drugs based on the soft drug approach

Abstract

In the general drug design process, one starts with a known bioactive molecule which is used as the lead compound and then undertakes structural moditiciltions either by the gmup or biotimctional moieties appmach in order to enhance the desired biological activity of the compound. This is most successful if one can identify the structural part responsible for the activity’. More recently, some other types of considerations were also involved in drug design, namely to improve delivery, distribution and pharmacokinetic properties of the drugs. In the general drug design process, however, little or no attention was paid to the metabolic disposition of the drugs. This is the case despite the fact that the toxicity of a number of bioactive molecules and drugs is due to their new %ructural pmperdes introduced during the design process. This means that the passible toxic metabolites or unwanted pharmacokinetic properties will generally be further enhanced when more active corn pounds are obtained. It is generally accepted that drugs, and particularly their metabolic processes, contribute to toxic processes by formation of active metaboliteP”. This phenomenon, the metabolic activation to reactive intennediates which covalendy bind to tissue macm molecules, is the initial step in the damage. The main reason that not much anention was paid to these processes is because the highly reactive metabolic intermediates cannot generally be idcntitied or observed as the excreted and identified metabolites are the end products of a long process. In order to impmve the therapeutic index for drugs. one has to be able to separate the activity and toxicity properties. Many drug designers believe that this is practically impossible and that most of the toxic side effects will parallel the increase ordecreaw in the desired pharmacological activity. One intemsting thought to avoid drug toxicity was provided by A&Ens. who suggested design of non-metabolizable drugs5. AI first sight this idea sounds really attractive as one would in this way avoid unwanted toxicity and the pharmacokia etics of the drug would b* rather simple, controlled only by renal excretion. We could call these kinds of non-metabolizable compnunds’harddrugs’. It is very unlikely, however, that one can ever succeed in designing ideal hard drugs. lt is wellknown [hat the body can attack and alter chemically quite stable suucmrcs and even if a drug was excreted 9&!25?41 unchanged. the unaccounted small potion might, and most likely would. cause toxicity by forming some reactive intermediates. It is also evident that one could achieve a complete inertness towards the metabolic process only if going to pharmacokinetic extremes. meaning drugs which arc rxtremcl?_ kdrrlphilic or extremely hydrophobic.