Medicinal Chemistry

A Timely Reassessment of Early Prediction in theBioavailability of Orally Administered DrugsTim Larsen and Andreas Link*

Keywords:hydrogen bonds · lipophilicity · medicinal chemistry ·metabolism · structure–activity relationships

The rapid and efficient biopharmaceut-ical classification of compounds underinvestigation is a major focus of thepharmaceutical industry.[1] The reasonsfor failure during and after the discoveryand development of novel chemicalentities (NCEs) are multifactorial.Whereas a lack of efficacy associatedwith improper validation of biologicaltargets or delays at the product portfoliolevel are not directly linked to the drugcandidate itself, many of the reasons forthe failure of a candidate can be tracedback to the structure of the molecule.For instance, pharmacokinetics, animaltoxicity, and the observation of adverseeffects in humans are all inextricablylinked to the chemical structure of thedrug. Therefore, the selection of theright compound to enter clinical devel-opment is critical. Medicinal chemistshave responded to this turn towardhigher quality through the implementa-tion of studies in absorption, distribu-tion, metabolism, elimination, and safe-ty into the discovery process.

In this context, the seminal retro-spective analysis of drug propertiesassociated with oral bioavailability per-formed by Lipinski and co-workers atPfizer in 1997 fell on fertile ground.[2]

The derived rule of thumb (“Rule ofFive”) rapidly became an importantfactor in the decrease of failures in earlydrug development projects.

Despite the practical value of thisstudy on the prediction of good oralabsorptivity for a drug candidate basedon a number of simple properties, theopportunities and needs for predictiveADMET (adsorption, distribution, me-tabolism, excretion, toxicology) havenever been greater.[1] Over the sevenyears in which Lipinski6s Rule of Fivehas been applied, its descriptive powerhas also revealed some shortcomings.The overly rigorous selection of drugcandidates to fit the rule may be anal-ogous to the evil deeds of Damastes,also known as Procrustes, the legendaryrobber of ancient Attica who lived in the

area of Eleusis. Nicknamed “the stretch-er”, he captured passing travelers to fitthem in one of his two beds. Shorttravelers were placed on a long bed, andtheir limbs were stretched until they fitproperly. Tall people were placed on asmall bed; extremities that hung overthe edge were amputated. This bloodyamusement was put to a stop by the heroTheseus, who finally killed Procrustes(Figure 1).[3] In a manner perhaps a littleless heroic than that of Theseus, severalresearch groups have tried to counteractthe overly rigorous or even erroneousapplication of the practical “Rule ofFive”. Many useful refinements have

Figure 1. Procrustes (Damastes), who captured travelers and brutally altered their body size tofit the bed in which they lay (upper right), was killed by Theseus. The center picture shows The-seus and the Minotaur; further deeds in the circle: Sinis, Phaia, Cercyon, Procrustes, Skiron,Marathonian Taurus (see cover picture Angew. Chem. Int. Ed. 2002, 41, issue 15). Kylix: 440–430BC, E 84, Copyright British Museum, London.

[*] T. Larsen, Prof. Dr. A. LinkLehrstuhl f6r Pharmazeutische/Medizinische ChemieErnst-Moritz-Arndt-Universit9t GreifswaldFriedrich-Ludwig-Jahn-Strasse 1717487 Greifswald (Germany)Fax: (+ 49)3834-86-4895E-mail: link@pharmazie.uni-greifswald.de

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4432 � 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim DOI: 10.1002/anie.200462888 Angew. Chem. Int. Ed. 2005, 44, 4432 –4434

been proposed as a result, including thesuggestion of additional parameterssuch as percent polar surface area(PSA), cyclicity, and the number ofrotatable bonds present.[4–6]

In an examination of the physico-chemical properties of 1100 drug candi-dates in the data records of formerSmithKline Beecham Pharmaceuticals,Veber et al. showed that the molecularweight cut-off at Mr = 500 alone doesnot significantly distinguish compoundswith poor oral bioavailability from thosewith acceptable values.[6] Whereas thisresult is in full accordance with Lipin-ski6s “Rule of Five”, it was found thatfor this special case only two newcriteria for a high probability of goodoral bioavailability were sufficient in-stead of the established four. First, theremust be 10 or fewer rotatable bonds andsecond, the polar surface area must beequal to or less than 140 B2 (or alter-natively, 12 or fewer H-bond donors andacceptors).

This helpful suggestion to decreasethe number of selection parameterswhich was derived from a biased propri-etary data set was misinterpreted as theinvention of two additional and broadlyapplicable selection criteria. The expan-sion of a rule of thumb usually watersdown the basic concept and leads to aloss of practical value. Hence, it wasargued that increasing the number ofprogression criteria on discovery proj-ects could aid in the identification ofquality compounds, but at the sametime, it would also increase the com-plexity of the discovery process and thusslow it down. As a result, patent life-times would decrease, costs would in-crease, and there would be a drop incompetitiveness in an aggressively com-petitive field.[1]

Therefore, instead of amendments,Leeson and Davis suggest a re-evalua-tion of the individual share of theparameters clogP (calculated logarithmof the partition coefficient in 1-octanol/water as a measurement of lipophilici-ty), molecular size expressed as Mr, andthe number of H-bond acceptors anddonors over time.[7] The resulting ques-tion is: Are there any time-relateddifferences in the physical properties oforally available drugs? Vieth et al. ob-served no meaningful correlation be-tween the year of launch (in the U.S.

between 1982 and 2002) and target class,Mr, or lipophilicity for oral drugs.[8]

The study by Leeson and Davisrevealed that drugs developed and mar-keted prior to 1983 have characteristicsthat differ significantly from newerNCEs. In a related study by Wenlocket al., drugs in various phases of clinicaldevelopment were analyzed. The resultsshowed that the mean molecular weightof compounds in the earlier phases ofdevelopment was significantly higherthan that of candidates in later phasesof development and marketed drugs.Similar trends were observed for thecharacteristics of the number of H-bondacceptors and rotatable bonds present.Furthermore, it was shown that themore lipophilic compounds tended tobe discontinued prior to phase III trials.These results highlight the well-knownphenomenon that during lead optimiza-tion, molecules tend to get larger, morecomplex, more lipophilic, and so on.This issue has already been clarified byTeague et al. through the highly originalconcept of “lead-likeness”.[9] Subse-quently, Wenlock et al. demonstratedthat the recognized resorption-limitingfactors are not historical artifacts but areunder physiological control.[10]

The investigation of Leeson andDavis sought to identify the physicalproperties that showed a historical shiftbetween drugs developed before 1983and newer drugs. Therefore, two setswere chosen: the first group containeddrugs launched prior to 1983 (864 com-pounds) and the other collection con-tained drugs launched between 1983 and2002 (329 compounds). The mean valuesof lipophilicity, percent polar surfacearea, and numbers of H-bond donors didnot change over the years. Hence, theseare probably the most important phys-ical properties for oral bioavailability,which is related to an underlying re-quirement for effective membrane per-meability.

Hydrogen-bond donors may there-fore be more important than acceptorsin this respect. This interpretation de-serves comment in current models ofmembrane permeability and should betaken into account in real and virtualdata bases, genetic algorithms, and fuzzylogic approaches.

On the one hand, it is necessary forthe associated hydrogen-bonded water

molecules to dissociate for sufficientmembrane permeability; on the otherhand, the drug candidate requires ad-equate solubility in lipids. Cell penetra-tion and absorption are highly depen-dent on the ability to form hydrogenbonds as well as on drug size andlipophilicity. As medicinal chemists re-alize intuitively, there is an importantand unchanging need to adjust thebalance of polar versus nonpolar prop-erties to allow sufficient gastrointestinalabsorption.[7] Abraham et al. cast doubton the assertion that the moderatelyhydrophilic solvent 1-octanol is an idealmodel of the hydrophobic core of themembrane phospholipid bilayer.[11]

The first experimental detection of alow-polarity alkane-like region at the 1-octanol/water interface was reportedrecently.[12] The implications of this phe-nomenon that has been termed “greasewall” for the partitioning of drugs in 1-octanol/water mixtures await furtherinvestigation. Concentrations of lipo-philic compounds at this interface mightresemble accumulation in cell mem-branes. However, the estimation of thebalance of polar versus nonpolar prop-erties with the established 1-octanol/water partition coefficients (and thederived values of logP) is far fromtrivial. The reason that logP valuesnevertheless add a substantial share topredictive power lies in their consider-able redundancy with respect to theother criteria discussed.

To date, in silico ADMET modelingis both a hot topic and difficult pros-pect.[13] Taking this insight into account,Lipinski6s Rule of Five will maintain itsvalue as a simple but highly practicablerule of thumb for years. With the resultsof Leeson and Davis taken into consid-eration, medicinal chemists may berewarded with a robustness and predic-tion power higher than those derivedfrom present methods.

Published online: June 28, 2005

[1] A. M. Davis, R. J. Riley, Curr. Opin.Chem. Biol. 2004, 8, 378 – 386.

[2] C. A. Lipinski, F. Lombardo, B. W.Dominy, P. J. Feeney, Adv. Drug Deliv-ery Rev. 1997, 46, 3 – 25.

[3] Ovid, Metamorphoses, Liber VII.[4] C. A. Bergstrom, M. Strafford, L. Laz-

orova, A. Avdeef, K. Luthman, P. Ar-

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tursson, J. Med. Chem. 2003, 46, 558 –570.

[5] J. Xu, J. Med. Chem. 2002, 45, 5311 –5320.

[6] D. F. Veber, S. R. Johnson, H. Y. Cheng,B. R. Smith, K. W. Ward, K. D. Kopple,J. Med. Chem. 2002, 45, 2615 – 2623.

[7] P. D. Leeson, A. M. Davis, J. Med.Chem. 2004, 47, 6338 – 6348.

[8] M. Vieth, M. G. Siegel, R. E. Higgs, I. A.Watson, D. H. Robertson, K. A. Savin,

G. L. Durst, P. A. Hipskind, J. Med.Chem. 2004, 47, 224 – 232.

[9] S. J. Teague, A. M. Davis, P. D. Leeson,T. Oprea, Angew. Chem. 1999, 111,3962 – 3967; Angew. Chem. Int. Ed.1999, 38, 3743 – 3748.

[10] M. C. Wenlock, R. P. Austin, P. Barton,A. M. Davis, P. D. Leeson, J. Med.Chem. 2003, 46, 1250 – 1256.

[11] M. H. Abraham, H. S. Chadha, G. S.Whiting, R. C. Mitchell, J. Pharm. Sci.1994, 83, 1085 – 1100.

[12] W. H. Steel, R. A. Walker, Nature 2003,424, 296 – 299.

[13] T. R. Stouch, J. R. Kenyon, S. R. John-son, X. Q. Chen, A. Doweyko, Y. Li, J.Comput.-Aided Mol. Des. 2003, 17, 83 –92.

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4434 � 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org Angew. Chem. Int. Ed. 2005, 44, 4432 –4434