The application of guidelines linked to the concept of drug-likeness, such as the 'rule of five', has gained wide acceptance as an approach to reduce attrition in drug discovery and development. However, despite this acceptance, analysis of recent trends reveals that the physical properties of molecules that are currently being synthesized in leading drug discovery companies differ significantly from those of recently discovered oral drugs and compounds in clinical development. The consequences of the marked increase in lipophilicity--the most important drug-like physical property--include a greater likelihood of lack of selectivity and attrition in drug development. Tackling the threat of compound-related toxicological attrition needs to move to the mainstream of medicinal chemistry decision-making.

Summary Ligand efficiency measures quantify the molecular properties, particularly size and lipophilicity, of small molecules that are required to gain binding affinity to a drug target. For example, ligand efficiency, is the binding free energy per heavy atom count (LE = G/HA) and lipophilic ligand efficiency (LLE = pIC 50 or KicLogP/D). There are additional efficiency measures for groups in a molecule, and for combinations of size and lipophilicity. The application of ligand efficiency metrics has been widely reported in the selection and optimisation of fragments, hits, and leads. In particular, optimisation of lipophilic ligand efficiency shows that it is possible to increase affinity and reduce lipophilicity at the same time, even with challenging 'lipophile-preferring' targets. Mean ligand efficiency measures of molecules acting at a specific target, when combined with their drug-like physical properties, is a practical means of estimating target 'druggability.' This is exemplified with 480 targetassay pairs from the primary literature. Across these targets correlations between biological activity in vitro and physical properties are generally weak, showing that increasing activity by increasing physical properties is not always necessary. Charles H. ReynoldsCharles Reynolds is currently President of Gfree Bio, a modeling and structure-based design company in AbstractThe judicious application of ligand or binding efficiencies, which quantify the molecular properties required to gain binding affinity for a drug target, is gaining traction in the selection and optimisation of fragments, hits, and leads. Retrospective analysis of recently marketed oral drugs shows that they frequently have highly optimised ligand efficiency values for their target. Optimising ligand efficiencies based on both molecular size and lipophilicity, when set in the context of the specific target, has the potential to ameliorate the molecular inflation that pervades current practice in medicinal chemistry, and to increase the developability of drug candidates.

The pharmaceutical industry remains under huge pressure to address the high attrition rates in drug development. Attempts to reduce the number of efficacy- and safety-related failures by analysing possible links to the physicochemical properties of small-molecule drug candidates have been inconclusive because of the limited size of data sets from individual companies. Here, we describe the compilation and analysis of combined data on the attrition of drug candidates from AstraZeneca, Eli Lilly and Company, GlaxoSmithKline and Pfizer. The analysis reaffirms that control of physicochemical properties during compound optimization is beneficial in identifying compounds of candidate drug quality and indicates for the first time a link between the physicochemical properties of compounds and clinical failure due to safety issues. The results also suggest that further control of physicochemical properties is unlikely to have a significant effect on attrition rates and that additional work is required to address safety-related failures. Further cross-company collaborations will be crucial to future progress in this area.

To be considered for further development, lead structures should display the following properties: (1) simple chemical features, amenable for chemistry optimization; (2) membership to an established SAR series; (3) favorable patent situation; and (4) good absorption, distribution, metabolism, and excretion (ADME) properties. There are two distinct categories of leads: those that lack any therapeutic use (i.e., "pure" leads), and those that are marketed drugs themselves but have been altered to yield novel drugs. We have previously analyzed the design of leadlike combinatorial libraries starting from 18 lead and drug pairs of structures (S. J. Teague et al. Angew. Chem., Int. Ed. Engl. 1999, 38, 3743-3748). Here, we report results based on an extended dataset of 96 lead-drug pairs, of which 62 are lead structures that are not marketed as drugs, and 75 are drugs that are not presumably used as leads. We examined the following properties: MW (molecular weight), CMR (the calculated molecular refractivity), RNG (the number of rings), RTB (the number of rotatable bonds), the number of hydrogen bond donors (HDO) and acceptors (HAC), the calculated logarithm of the n-octanol/water partition (CLogP), the calculated logarithm of the distribution coefficient at pH 7.4 (LogD(74)), the Daylight-fingerprint druglike score (DFPS), and the property and pharmacophore features score (PPFS). The following differences were observed between the medians of drugs and leads: DeltaMW = 69; DeltaCMR = 1.8; DeltaRNG = DeltaHAC =1; DeltaRTB = 2; DeltaCLogP = 0.43; DeltaLogD(74) = 0.97; DeltaHDO = 0; DeltaDFPS = 0.15; DeltaPPFS = 0.12. Lead structures exhibit, on the average, less molecular complexity (less MW, less number of rings and rotatable bonds), are less hydrophobic (lower CLogP and LogD(74)), and less druglike (lower druglike scores). These findings indicate that the process of optimizing a lead into a drug results in more complex structures. This information should be used in the design of novel combinatorial libraries that are aimed at lead discovery.

The optimization of low-potency leads into drugs is often accompanied by an increase in molecular weight (M(r)) and lipophilicity, as a consequence of affinity enhancement. Hits with affinity at µM levels discovered by screening leadlike libraries allow scope for this optimization process, as shown schematically by the distributions of M(r) for a leadlike library (1), oral drugs (2), and a typical combinatorial chemistry library (3). y=percentage with a particular molecular weight.

The process of drug discovery applies rigorous selection pressures. Marketed oral drugs will generally possess favorable physiochemical properties with respect to absorption, metabolism, distribution, and clearance. This paper describes a study in which the distributions of physiochemical properties of oral drugs in different phases of clinical development are compared to those already marketed. The aim is to identify the trends in physiochemical properties that favor a drug's successful passage through clinical development and on to the market. Two libraries were created, one of current development oral drugs and one of marketed oral drugs. Statistical analysis of the two showed that the mean molecular weight of orally administered drugs in development decreases on passing through each of the different clinical phases and gradually converges toward the mean molecular weight of marketed oral drugs. It is also clear that the most lipophilic compounds are being discontinued from development.

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Comparisons of the calculated physicochemical properties of oral drugs launched prior to 1983 (864 drugs) and between 1983 and 2002 (329 drugs) show that mean values of lipophilicity, percent polar surface area and H-bond donor count are the same, suggesting that these are the most important oral druglike physical properties. In contrast, mean values of molecular weight and the numbers of O + N atoms, H-bond acceptors, and rotatable bonds and rings have increased in 1983-2002 drugs (by 13-29%). Analysis of the 1983-2002 oral drugs by therapy area shows that antiinfectives and nervous system drugs have the most extreme physical property profiles. Cardiovascular drugs show increasing molecular weight with year of publication, primarily a consequence of focusing on clinically proven mechanisms, with limited chemical diversity. Drug classes other than antiinfectives show comparable distributions of lipophilicity, suggesting that this property in oral drugs is important irrespective of the drug's target. The results suggest that the balance between polar and nonpolar drug properties is an important, unchanging feature of oral drug molecules.