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Medicinal chemistry’s quest for potent drug candidates has resulted in molecules that are too large and too lipophilic for their own good

Medicinal chemistry is at the heart of the drug discovery process, and the creativity of medicinal chemists in identifying the best leads and then optimising them on a complex landscape of constraints is often the defining characteristic of successful drug discovery campaigns. It’s a process that more often resembles an unpredictable journey on a chaotic surface rather than a quantitative and predictive science.

Despite the increase in biology and chemistry knowledge worldwide, the discovery of effective and safe new drugs seems to become harder rather than easier. Some of this challenge is due to increasing demands for safety and novelty, but some of the risk involved in this should be controllable if we had more effectively learnt from our failures. Mike Hann has coined the term ’molecular obesity’ in a review in the journal MedChemComm  to describe our tendency to build potency in the molecules by the inappropriate use of lipophilicity, which leads to the premature demise of drug candidates. 

Bioavailability used to be a leading cause of failure in drug discovery, but more recently this appears to have been over taken by toxicology. This is probably because pharmacokinetic issues are better understood and formulations of compounds have improved. Some of this improvement in getting compounds into the body (and keeping them there) may have contributed to the rise in attrition due to toxicological issues as the body responds to chemical entities that are ’forced’ into the body. 

Thus by using formulation technologies to deliver inappropriate molecules we may have only delayed the realisation that a molecule is inappropriate to a more expensive part of the drug discovery activity. The usual response of the body to lipophilic foreign molecules is to try to make them more polar via metabolism so they can be excreted. Medicinal chemists often have to make their lipophilic and insoluble compounds more metabolically stable to prolong their duration of action. This can put enormous demands on a compound’s profile, especially if once-a-day dosing is being sought as the target product profile. Blocked metabolism means the body will need to find more extreme ways of removing the compound, often inducing more high potential and thus intrinsically more reactive and toxic species. 

Bordering on an addiction 

Excess molecular weight and lipophilicity are not conducive to the ultimate success of compounds in the drug discovery process, so why is it that we so readily find ourselves at the limits or beyond of what is the statistically safer zone? One of the key drivers that leads to this situation is our perceived need for potency (bordering on an addiction) and the fact that potency can often be most easily gained by increasing lipophilicity. We like potency in our molecules for a number of reasons and it is worth examining why this is. 

One of the basic tenets of medicinal chemistry is that increasing ligand potency leads to increased specificity and hence to an improved therapeutic index. Finding appropriate interactions by increasing matched complexity is essential for optimising weak leads to give increased potency. However, if complexity is introduced unnecessarily it does nothing to build the specificity, and can introduce the opportunity for recognition at other targets. 

Potency can compensate for low bioavailability in that the small portion of, for example, a poorly absorbed drug that does get into the circulation will at least have a chance of being efficacious if it has high molar potency. However this brings a high risk in that the part of the high dosage that is not being used effectively is available to cause off-target issues. 

The dangers of molecular obesity 

Increasing molecular weight and lipophilicity in our hunt for potency results in molecules that could be described as obese; they have become too large and too lipophilic for their own good. This addiction to molecular obesity represents a high risk to the future health of the molecule as a drug candidate.