CHEMISTRY & BIODIVERSITY – Vol.

6 (2009) 1887

REVIEW

Recent Advances in Physicochemical and ADMET Profiling in Drug

Discovery
by Jianling Wang* and Suzanne Skolnik
ADME Profiling Cambridge, Metabolism and Pharmacokinetics, Novartis Institute for Biomedical
Research, 250 Mass Ave, Cambridge, MA 02139, USA
(phone: 001 617 871 7140; fax: 001 617 871 7061; e-mail: jianling.wang@novartis.com)

The drastic increase in the cost for discovering and developing a new drug along with the high
attrition rate of development candidates led to shifting drug-discovery strategy to parallel assessment of
comprehensive drug physicochemical, and absorption, distribution, metabolism, excretion, and toxicity
(ADMET) properties alongside efficacy. With the proposal of a profiling paradigm and utilization of
integrated risk assessment, one can exponentially enhance the predictive power of in vitro tools by taking
into consideration the interplay among profiling parameters. In particular, this article will review recent
advances in accurate assessment of solubility and other physicochemical parameters. The proper
interpretation of these experimental data is crucial for rapid and meaningful risk assessment and rational
optimization of drug candidates in drug discovery. The impact of these tools on assisting drug-discovery
teams in establishing in vitro – in vivo correlation (IVIVC) as well as structure – property relationship
(SPR) will be presented.

Abbreviations
ADMET: Absorption, distribution, metabolism, excretion, and toxicity; CE: capillary electrophoresis;
FaSSIF: fasted-state simulated intestinal fluid; FeSSIF: fed-state simulated intestinal fluid; GI:
gastrointestinal; HT: high throughput; IAM: immobilized artificial membrane; IVIVC: in vitro – in vivo
correlation; MEEK: microemulsion electrokinetic chromatography; NCE: new chemical entity; PSA:
polar surface area; PD: pharmacodynamic(s); PK: pharmacokinetic(s); SGA: spectral gradient
analyzer; SGF: simulated gastric fluid; SIF: simulated intestinal fluid; SPR: structure – property
relationship.

1. Introduction. – Recently, the chemical space of new therapeutic targets for unmet
medical needs or for alternative pathways has shifted the molecular properties of NCEs
towards higher molecular weight, greater lipophilicity, and more promiscuity against
metabolic enzymes and other non-therapeutic targets [1] [2]. These have posed great
challenges in drug discovery and promoted parallel assessment of efficacy and
comprehensive ADMET properties of NCEs in drug discovery to optimize properties
and foresee liabilities of drug candidates [3 – 5]. Multiple in silico, in vitro, and in vivo
ADMET filters are being developed and implemented in various stages of the drug
discovery and development process to alert chemists of potential ADMET issues in the
clinic [6 – 9]. While computational approaches have advantages in cost-saving and no
sample requirement [10 – 13], in vitro ADMET assays offer the first experimental tools

 2009 Verlag Helvetica Chimica Acta AG, Zrich

1888 CHEMISTRY & BIODIVERSITY – Vol. 6 (2009)

to rank and prioritize NCEs, as well as to tackle the mechanistic pathway in the early
discovery phase.
It is widely accepted that ionization constant, lipophilicity, and solubility are among
the key physicochemical parameters critical for the predictability of drug bioavail-
ability, and significantly affect drugs behaviors in many PK, PD, and toxicological
aspects (Fig. 1). As a result, there are drastically growing interests from both industry
and academia in investigating the computational and experimental approaches to
accurately assess these properties and explore their impact on the discovery and
development of new drugs (Fig. 2). The current report briefly reviews the experimental
approaches to assess these parameters in drug-discovery phases in conjunction with
selected in silico tools, with advantages and limitations outlined for the benefit of users.
In addition, case studies are presented to demonstrate the impact of these parameters
on PK, PD, and safety concerns of NCEs.

Fig. 1. Schematic presentation of the relationship and interplay of physicochemical properties with in vivo
drug pharmacokinetics/pharmacodynamics and exposure

2. Physicochemical Parameters. – 2.1. Ionization constant (pKa ). Ionization

constant, pKa , is a useful thermodynamic parameter to modulate the charge state
and eventually solubility, permeability, and other key properties of drug candidates.
Therefore, accurate assessment of pKa and ionization process of NCEs allows for
properly interpreting and predicting ADME properties due to the pH gradient of 1.0 –
7.0 from human stomach to GI tract [14]. In addition, pKa information is useful for
establishment of therapeutic SAR for complementary charged sites in drug discovery.
Computationally or experimentally derived pKa data are also required in the
determination of solubility – pH profiling [15], lipophilicity [16], and other drug
properties.
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Fig. 2. Number of publications citing ionization constant, lipophilicity, and solubility of drugs and
NCEs as counted by SciFinder. There is an increasing trend toward reporting technical advances and
applications in all three fields, especially for solubility, in the past decade.

While pKa for marketed drugs can be properly predicted by in silico tools owing to
the high dependence primarily on the molecular structure itself, the prediction is less
accurate for early discovery NCEs (Fig. 3, a). The deterioration in predictivity for
discovery NCEs may be attributed to the unique structural moieties, leading to R2 ¼
0.77 for a collection of 216 Novartis discovery NCEs against data from potentiometric
titration method (see below), in comparison to commercial drugs (R2 ¼ 0.994 for
marketed drugs, as reported in [17]), thereby justifying the need for in vitro deter-
mination.
A range of experimental approaches [5] [9] [18] is widely accepted in the different
stages of drug discovery and development process. Potentiometric titration [14] offers a
relatively reliable and automatic approach to measure pKa but appears applicable in
late discovery and development phases due to its limited capacity and the large amount
of materials required (mg in powder). Despite being recognized as the gold-standard
experimental method, challenges still exist in handling poorly water-soluble NCEs.
Several methods were, therefore, adopted to meet the required capacity, turn-
around time, cost, and sample restrictions in early discovery. Box et al. [17] reported a
HT method to measure pKa using mixed-buffer linear pH-gradient system, followed by
UV readout, referred to as SGA by Sirius Analytical Instruments, Ltd. It demonstrated
a robust, cost-effective, and less labor-intensive way to assess pKa . A very good
predictivity to the gold-standard potentiometric titration was reported for a set of
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Fig. 3. Comparison of pKa data measured using a potentiometric method (GlpKa ) with those a) from in
silico prediction (via the ACD v.9 software) and b) determined with a HT-pKa approach (on SGA), from
the same set of 216 Novartis discovery NCEs. Apparently, HT-pKa measurement offers much better
predictivity toward the data derived via the gold-standard method for challenging discovery compounds.

marketed drugs [19]. Indeed, a good correlation to potentiometric titration method was
obtained using the very same test set of 216 discovery NCEs mentioned above, with R2
improvement to 0.98 (Fig. 3, b). This method, however, is only feasible for NCEs with
UV-spectroscopic variation associated with the ionization process, leading to ca. 70%
success rate when testing NCEs at Novartis. Historically, some of the dropouts were
followed up using potentiometric titration method in our laboratories. Capillary
electrophoresis (CE) [20] [21] in junction with MS readout [22] [23] assesses pKa using
the mobility of NCEs in CE. The method seems to have high sensitivity and good
success rate, and is feasible for NCEs with poor aqueous solubility. It certainly requires
higher investment than SGA approach in equipment and manpower involvement for
MS analysis. So far, good correlations were reported for marketed drugs between CE-
MS data and those in literature [22] [23], but it may be worthy to extend the evaluation
to discovery NCEs. Measurement of pKa was also investigated using reverse-phase
high-performance liquid chromatography (RP-HPLC) by programmed increase of the
eluting strength and pH gradient [24]. The method appears to work but requires careful
control of the eluting pH gradient. While different HPLC protocols are needed for
acids and bases, higher variations to literature values may be expected for bases with
high pKa values and acids with low pKa values.
As mentioned previously, ionization properties are useful for understanding
binding of NCEs to targets. However, in some cases the therapeutic pharmacophore
may overlap with a molecular moiety that also inhibits the hERG potassium channel
(encoded by the human ether-a-go-go related gene), leading to cardiac complications
[25]. Many of the compounds that block the hERG channel contain basic N-atoms.
Therefore, one strategy to attenuate hERG potency is to modulate the basicity of this
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moiety. While correlations are expected to be weak for a large set of diverse
compounds, a strategy to modulate pKa may be more successful on a specific scaffold or
series (reviewed in [26]). It should be noted that other factors such as lipophilicity are
important in modulating hERG inhibition [27], as exemplified in the next section.
2.2. Lipophilicity (log P/D). Lipophilicity is a determinant to quantitatively
describe a NCEs ability to partition in the oily phase or biological membranes. It is
also frequently utilized in explaining behavior of some NCEs in the ADMET assays.
Practically it is expressed as the logarithms of partition coefficient or distribution
coefficient (log P or log D) of NCEs in a lipophilic phase (e.g., octan-1-ol) and aqueous
phase. Frequently, project teams are developing lipophilicity-modulated SAR, as some
pharmacologic or biologic activity often correlates with log P of NCEs. As one of the
key parameters outlined in Rule of Five [28], lipophilicity greatly affects solubility,
permeability, and other drug properties. From formulation perspective, it is difficult to
formulate NCEs with low distribution coefficient (log D) at physiological pH.
The conventional gold-standard approach to quantify the log P or log D values was
referred to as the shake-flask method, which is very time-consuming and labor-
intensive, thereby not feasible in early discovery [29]. Meanwhile, the dual-phase
potentiometric titration approach is widely accepted as gold-standard method in drug
discovery and development phases [14]. Using this approach, however, the quality of
log P data will rely greatly on the accurately determined pKa values, and, therefore,
requires an ionization center. In addition, this method, albeit automated, has limited
capacity and is, therefore, not conceivable for HT approaches in early discovery. It
should be mentioned that precaution may be taken to handle NCEs with high
lipophilicity and low aqueous solubility to avoid overestimated log P caused by the shift
in the Bjerrum plot as a result of precipitation instead of partitioning.
An alternative approach using HPLC, known as eLogP, was reported for the
determination of log P for both neutral and ionizable NCEs [30]. With octan-1-ol as a
co-eluent, log P values can be extracted using a capacity factor, without requiring an
ionizable group. Excellent correlations to gold-standard methods were reported by
different groups on marketed drugs [30] [31]. In addition, the eLogP method shows
high sensitivity for log P determination and is applicable to low-soluble compounds.
Attention may be paid to the potential interference of octan-1-ol to the elution process
and retention time. There was an attempt to miniaturize the traditional shake-flask
method in 96-well plate in conjunction with RP-HPLC readout for log D determination
[32]. While a reasonable correlation was reported using marketed drugs, the method
has challenges in dealing with NCEs with poor aqueous solubility and extremely high
log P. Microemulsion electrokinetic chromatography in combination with CE
(MEEKC-CE) has been adopted for measuring log P in discovery, and its quality
relies on the proper selection of microemulsion materials [33]. By using sodium
dodecyl sulfate for microemulsion, Jia et al. [34] reported a good correlation of the
MEEKC-CE log P values to literature data from 13 marketed drugs. However, the
correlation deteriorated when applied to discovery NCEs. While this method shows
good sensitivity for log P measurement and is also applicable to low-soluble NCEs, it
may be problematic for NCEs with high log P values (e.g.  5, where in MEEKC
separation from the micelle marker is difficult to resolve) or high pKa values (e.g.  10,
where some basic NCEs do not fully partition as a result of partially charged state) [34].
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In Novartis, a HT-log P method was developed using artificial membrane

preparations conceivable for needs in early drug discovery [16]. In contrast to the
conventional artificial membrane model where hexadecane was used for assessing GI
permeability, octan-1-ol was utilized here for membrane preparation of log P
determination. The apparent permeability obtained at a pH corresponding to a
compounds neutral species shows a relationship to the log Poct data derived in gold-
standard protocols. It is worthy to mention that the quality of the HT-log P data from
this approach is to a great extent governed by the sensitivity of readout. For instance,
the correlation of log P data derived by artificial-membrane approach to those from the
gold-standard method has been appreciably improved by shifting from UV plate reader
(R2 ¼ 0.453) to LC/MS (R2 ¼ 0.731) on a collection of Novartis discovery NCEs (Fig. 4).
Overall, it is a robust and less labor-intensive method conceivable for early drug
discovery, but will require relatively high investment in LC/MS as well as measured or
predicted pKa data to define the pH where the tested NCE is neutral.

Fig. 4. Comparison of log P data measured using a potentiometric method (GlpKa ) or the eLogP method
with those from an octan-1-ol-membrane method (HT-log P). a) UV Detection on 96-well microtiter
plates was applied; b) LC/MS detection was applied to quantify the compound fraction that passed
through the octan-1-ol membrane, leading to calculation of log P. Improved predictivity to log Poct was
achieved using more sensitive LC/MS detection.

Similar to the HT-log P method, IAM coupled with HPLC seeks to increase
throughput. However, IAM differs from the above traditional isotropic octan-1-ol/H2O
solvent systems in that it utilizes an anisotropic media to include membrane interaction
with both neutral and charged drug species. Specifically, the IAM is prepared by
covalently binding phosphatidylcholine residues to silico particles to mimic a fluid
phospholipid bilayer. Earlier efforts were devoted to correlating IAM indices with cell
or skin permeability, blood – brain barrier permeation, or intestinal absorption [35].
Recent research focuses on congeneric series for improved SARs. For example,
Pehourcq et al. [36] correlated IAM capacity factors of arylpropionic acids with
pharmacokinetic data, including volume of distribution, plasma protein binding, and
 CHEMISTRY & BIODIVERSITY – Vol. 6 (2009) 1893

half-life (correlation coefficient 0.8 – 0.9). The authors found that IAM retention was in
fact correlated to log P/log D 7.4 results, while this is not always the case depending on
the degree of protonation and hydrophilicity [35] [37] [38].
Measured lipophilic parameters are expected to be more accurate than calculated
cLogP or cLogD, whose accuracy will also depend on ionization prediction [39].
Nevertheless, calculated lipophilicity is frequently used in drug discovery, while best
practice may be to establish a correlation between calculated and measured values
before relying solely on predictions for SAR. Calculated log P is often a part of
additional pharmacokinetic parameter modeling. In Fig. 5, a classification model for
passive absorption based on cLogP and PSA [40] separates NCEs based on their rank
in an artificial-membrane permeability assay (PAMPA). Initially tested with Pharma-
copia drug-discovery compounds in the original publication, the model also performs
well for Novartis NCEs. Most of the highly permeable compounds (85%) in Fig. 5 fall
within the area defined by well-absorbed marketed drugs, which makes this in silico
tool useful for pre-filtering compounds for in vitro measurements or for drug design.

Fig. 5. Novartis NCEs (n ¼ 2500) plotted as a function of cLogP and polar surface area (PSA). The open
squares (&), plus signs (þ), and letter (  ) are high, medium, and low permeability, respectively, ranking
in a PAMPA assay. Eighty-five percent of highly ranked NCEs fall within the inner ellipse, as defined by
marketed drug oral absorption.

While lipophilicity is one of the key parameters for many compounds to achieve
potency and acceptable oral absorption, increasing lipophilicity of NCEs may lead to
insufficient solubility, increased non-specific binding, and higher promiscuity. Recently,
Leeson and Springthorpe [1] reported the increasing safety concerns for industry
compounds with inflated physical properties. It is best practice to identify lead
compounds that are smaller and more hydrophilic to allow room for chemical
optimization. Fig. 6 presents two Novartis drug-discovery programs whose lead
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compounds were profiled over a series of two months. Reducing lipophilicity not only
optimized clearance properties towards improved exposure for one program (a), but
also reduced hERG binding liability in another program (b).

Fig. 6. a) Optimization of rat extraction ratio from microsomal stability assay vs. cLogP for a series of 22
lead optimization compounds in one Novartis program. b) hERG IC50 Values [mm] measured in the radio-
ligand binding assay for a second Novartis program where binding affinity was reduced with decreased
cLogP for 23 lead optimization compounds.

2.3. Solubility and Dissolution. Being a critical parameter affecting both in vitro and
in vivo attributes, solubility measures the ability of drug candidates to dissolve and
remain in aqueous or other physiological media. Multiple solubility expressions are
available that are noticeably distinct by collection methods and also by their potential
applications (mostly referred to as thermodynamic or equilibrium solubility).
Thermodynamic solubility, commonly derived after a long incubation using the
shake-flask approach, is frequently employed to assess the in vivo exposure of test
compounds, to present in vitro – in vivo correlations, as well as to understand the
interplay among ADMET parameters. In contrast, kinetic or apparent solubility is
determined with a short incubation time in aqueous media in the presence or absence
of co-solvents such as DMSO for characterizing and qualifying biological and ADMET
profiling assays where insoluble NCEs may precipitate under similar conditions [5].
Intrinsic solubility can be used to assess the solubility of NCEs as neutral species and
predict its impact on permeability, which is believed to correlate better with the
availability of neutral molecules in solution.
Multiple approaches are employed to develop in silico models for predicting
thermodynamic solubility. However, most of the models available at present were not
very predictive due to complex interplay among H-bond acceptors and donors,
conformational effects, and crystal-lattice energy for NCEs. Pharmacophore models
have advantages over mathematic models in that they differentiate soluble moieties
from insoluble ones in the calculation, which is feasible for establishing SPR.
Practically, the predictivity of solubility models relies appreciably on the drug-likeness
of the selected training set as well as the physiologically relevant solubility range (e.g.,
10  4 – 101 g/l instead of 10  12 – 103 g/l presented by some models) [41] [42]. Some in
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silico predictions may require other physicochemical parameters not always available
in early drug discovery, such as log P or melting point [43] [44].
The conventional thermodynamic solubility protocol starting with solid material,
also referred to as saturation shake-flask method, reflects not only the molecular
interactions of NCEs in solution phase but also the solid packing insights (polymorph
state) [5] [45] [46]. The assay typically involves a long (24 – 72 h) agitated incubation of
NCE powders in a designated buffer at a specific temperature, followed by phase
separation (of saturated solution from solute) and quantification [47] [48]. This method
is considered the gold standard for solubility determination by industry and US FDA,
and is widely utilized to project the in vivo GI absorption [49] and bioavailability of
NCEs together with in vitro permeability and metabolic clearance data. This approach,
however, is time-consuming and labor-intensive, thereby not conceivable for HT-
solubility screening in early discovery but ideal for compounds in late discovery or in
development phase, when only a small number of compounds but with sufficient
amount of materials are available in crystalline forms.
Alternative approaches were evaluated to meet the needs in lead-optimization
phase without noticeably jeopardizing the quality of the data. For instance, kinetic
solubility, albeit simpler and feasible in HT format, fails to properly project the
solubility impact on in vivo exposure. Other approaches involving (0.5 – 5%) DMSO in
the streamlined HT-solubility process may also lead to substantially overestimated
equilibrium solubility [48]. In contrast, kinetic solubility derived at the reduced
incubation time (e.g. 0.5 – 3 h) may reflect a snapshot of the incomplete dissolution,
leading to underestimated solubility. Fig. 7 presents kinetic solubility vs. shake-flask
solubility for a set of Novartis NCEs and illustrates the lack of correlation between the
two approaches. Unfortunately, the DMSO-mediated overestimation and incubation
time-related underestimation of solubility are compound-specific which is difficult to
correct due to lack of direct SPR between the solubility variability and NCEs structure.
Several miniaturized platforms with different throughput have been evaluated to
assess equilibrium solubility using Uni-Prep filter chamber [50] [51], circulation pump
[52], and vials [53] [54]. In 2007, Zhou et al. [48] reported a true HT and miniaturized
equilibrium solubility approach utilizing mini-prep vials and fast HPLC. This novel
approach addressed most of the caveats encountered by the kinetic or semi-
equilibrium solubility approaches, thereby exhibiting an excellent agreement with
the conventional shake-flask approach for not only commercial drugs but also exigent
NCEs in early drug discovery. Recently, the miniaturized equilibrium solubility
platform has been successfully migrated to the 96-well plate format, showing a
reasonable agreement with the shake-flask method (unpublished data).
While HT-equilibrium solubility data are designed to help establish solubility SPR
toward the improved in vivo exposure, practically they sometimes may be misused.
Typical cases are to overuse equilibrium solubility derived at acidic aqueous buffer
(e.g., pH 1.0) to rank discovery NCEs and to project their in vivo dissolution, without
considering the nature of the NCEs. Unfortunately, the majority of discovery NCEs is
either bases or ampholytes (54 and 25%, resp., in Novartis; see Fig. 8, a), which mostly
results in high solubility only at acidic pH (Fig. 8, b), instead of at pH where drug
substances are absorbed in GI tract. Therefore, solubility SPR practice at acidic pH
commonly leads to over-optimism and unpleasant surprise of solubility burden at the
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Fig. 7. A comparison of solubility data, from a collection of 389 discovery NCEs, measured by a
conventional shake-flask approach (thermodynamic solubility) with those assessed via a kinetic method
(kinetic solubility). The former starting from powder was agitated for 24 – 72 h in vials and quantified via
HPLC-UV. The kinetic protocol, however, was determined on 96-well plates by adding DMSO stock into
buffer (0.5 – 2% DMSO in the buffer) and monitoring the precipitation of NCEs from solution using
nephelometric readout after a short (10 – 30 min) incubation time. Clearly, the kinetic solubility should
not be used to predict thermodynamic solubility due to lack of correlation between the two approaches.

development nomination phase, when NCEs have a chance to be fully characterized.

This will not only cause substantial delay in project progress but also create difficulty
for structure optimization, as most of the chemical spaces are well-defined at this stage
by pharmacologic or other ADMET properties. One approach to avoid this issue is not
to offer the HT-equilibrium solubility data at acidic pH until nomination of develop-
ment candidates at late discovery phase.
Another challenge to use HT-equilibrium solubility to build SPR lies in the large
population of low-solubility data derived at neutral pH and lack of direct correlation to
in vivo exposure. This observation should not be surprising, as equilibrium solubility in
aqueous buffers offers simplified determinants to flag solubility risks of NCEs, while,
practically, the composition of intestinal fluid is far more complex. To address this issue,
pharmaceutical industry is moving toward predicting the in vivo performance of a drug
subsequent to an oral dose using SIF, SGF, FaSSIF, and FeSSIF [55 – 60]. FaSSIF and
FeSSIF contain a mixture of bile salts and surfactants (such as sodium taurocholate)
mimicking the physiological media in human stomach and intestine, and promoting
wetting process in GI tract [55]. Therefore, these biorelevant media are powerful in
identifying the dissolution limiting factor to absorption and ultimately help establish
IVIVC. For example, a series of discovery NCEs with medium-to-high in vitro
permeability and metabolic stability all show poor correlation between equilibrium
solubility obtained in aqueous buffer and rat bioavailability (unpublished data). In this
case, all aqueous-solubility data cluster at the low end of the HT-equilibrium solubility
 CHEMISTRY & BIODIVERSITY – Vol. 6 (2009) 1897

Fig. 8. Distribution of acids (AH), bases (B), ampholytes (XH), and neutral compounds (N) from a
random selection of 2660 Novartis NCEs shows that the majority are basic compounds (a). The percentage
of highly soluble compounds by distribution of species (b) indicates that bases and ampholytes may be
over-optimistically characterized as highly soluble at pH 1.0 rather than at physiological pH.

assay and are difficult to differentiate, despite significant modifications in chemistry.

Some of them, however, show drastically improved solubility in FaSSIF, also toward
better agreement with in vivo exposure derived in rat PK studies.

3. Conclusions. – Nowadays, in silico, in vitro, and in vivo ADMET tools constitute

an integrated part of modern medicinal chemistry and drug discovery with respect to
the early assessment of drug-exposure profile and safety performance. The full
awareness of the benefits and limitations of each tool assures the right questions to be
answered using right tools at the right time. For instance, equilibrium or thermody-
namic solubility should be chosen to predict solubility-driven drug absorption, whereas
HT-kinetic solubility is applicable for qualifying biological and in vitro ADMET data
derived with short incubation time in DMSO-containing media [5] [48]. Foremost,
continuous education of ourselves, not only on what tools are available but how to
properly utilize them, is a must, as the knowledge in ADMET profiling is drastically
evolving, and many decisions previously made in development or even clinical phases
are moved up to early drug discovery. Second, the comprehensive ADMET profiling
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should be applied early enough in lead-selection and optimization phases, in a proactive

manner. Not only is this because optimizing ADMET properties is considered more
difficult and complex than optimizing potency, but also due to the limited chemical
space for further optimization in drug properties, once lead NCEs are optimized by
potency at the primary target. Rational profiling rather than box-checking strategy is
found more efficient in dialing out the key ADMET issues where one should avoid
rejecting NCEs based simply on poor ranking from one profiling assay, or a risk flag
without thoroughly understanding the mechanistic relevance and potential impacts.
Finally, it is worthwhile to review the success stories where rational ADMET profiling
helped advance the candidates and, more importantly, the failures of terminated
chemical series by identifying the causes of errors. The latter typically offers more
constructive feedback to the constantly evolving ADMET profiling process.

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Received March 30, 2009