Decreasing HepG2 Cytotoxicity by Lowering the Lipophilicity of Benzo[d]oxazolephosphinate Ester Utrophin Modulators

Article abstract of DOI:10.1021/acsmedchemlett.0c00405

Utrophin modulation is a disease-modifying therapeutic strategy for Duchenne muscular dystrophy that would be applicable to all patient populations. To improve the suboptimal profile of ezutromid, the first-in-class clinical candidate, a second generation

Full text of DOI:10.1021/acsmedchemlett.0c00405

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Letter
Decreasing HepG2 Cytotoxicity by Lowering the Lipophilicity of
Benzo[d]oxazolephosphinate Ester Utrophin Modulators
Maria Chatzopoulou, Enrico Emer, Cristina Lecci, Jessica A. Rowley, Anne-Sophie Casagrande, Lee Moir,
Sarah E. Squire, Stephen G. Davies, Shawn Harriman, Graham M. Wynne, Francis X. Wilson,
Kay E. Davies, and Angela J. Russell*
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ABSTRACT: Utrophin modulation is a disease-modifying ther-
apeutic strategy for Duchenne muscular dystrophy that would be
applicable to all patient populations. To improve the suboptimal
profile of ezutromid, the first-in-class clinical candidate, a second
generation of utrophin modulators bearing a phosphinate ester
moiety was developed. This modification significantly improved
the physicochemical and ADME properties, but one of the main
lead molecules was found to have dose-limiting hepatotoxicity. In
this work we describe how less lipophilic analogues retained
utrophin modulatory activity in a reporter gene assay, upregulated
utrophin protein in dystrophic mouse muscle cells, but also had
improved physicochemical and ADME properties. Notably, ClogP
was found to directly correlate with pIC50 in HepG2 cells, hence leading to a potentially safer toxicological profiles in this series.
Compound 21 showed a balanced profile (H2K EC50: 4.17 μM, solubility: 477 μM, mouse hepatocyte T1/2 > 240 min) and
increased utrophin protein 1.6-fold in a Western blot assay.
KEYWORDS: Duchenne muscular dystrophy, utrophin upregulation, hepatotoxicity, phosphinate esters
uchenne muscular dystrophy (DMD) is an X-linked
Dneuromuscular disorder caused by loss of function
mutations on the dystrophin gene.1 Though classified as a
rare disease, it is one of the most common fatal genetic
diseases affecting children.1 Dystrophin is a critical component
of the dystrophin-associated protein complex (DAPC)
connecting the internal cytoskeleton to the surrounding
Figure 1. Structures of ezutromid (1), SMT022357 (2), and
SMT022332 ((+) enantiomer, 3).
extracellular matrix. In the absence of functional dystrophin,
the muscles gradually degenerate, leading to inflammation,
fibrosis, and failed cycles of regeneration.2,3
Phase 1 clinical trials.11−13 Encouraging interim 24-week data
More than 30 years after the discovery of dystrophin,4 there
in a Phase 2 trial (NCT02858362, Summit Therapeutics PLC,
PhaseOut DMD) showed increase of utrophin protein and
reduction of muscle fiber damage. However, the primary and
is still a paucity of treatment options for the disease, as the only
disease-modifying therapeutics are targeting specific subpopu-
lations and the standard of care is aimed mostly to alleviate the
inflammation and other secondary effects. A promising
therapeutic strategy that would be both disease modifying
and could target all patient subpopulations is functional
secondary clinical end points were not met at the end of the
trial and development of ezutromid was discontinued.14 The
lack of sustained efficacy has been attributed to extensive
metabolism of ezutromid and induction of CYP1A (ezutro-
replacement of dystrophin with its structural paralogue
utrophin.2 Data from transgenic animal models5−7 led to the
Received: July 20, 2020
Accepted: October 26, 2020
initiation of drug discovery programs, the most advanced of
which progressed to Phase 2 proof of concept clinical trials.
Ezutromid (Figure 1, 1), formerly SMT C1100, a utrophin
modulator initially discovered via a HTS using a firefly
luciferase (Fluc) reporter gene assay,8,9 led to promising results
in animal models of DMD10 and a safe profile in multiple
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a
Scheme 1. General Synthetic Routes to Phosphinate Esters
a
Reagents and conditions: (i) BnBr, K2CO3, acetone, 60 °C, 6 h, (yields 97% and 74% for 4 and 5, respectively); (ii) EtPH(O)OH, Pd(OAc)2,
Xantphos, DIPEA, DME/toluene, 90 °C, 2 h, (yields 71−98%); (iii) (1) SOCl2, DMF, 70 °C, 1−2 h; (2) DIPEA, MeOH, DMAP, CH2Cl2, rt, 30
min (yields 41−85%) or MeOH, rt, 15 min for 9 (yield 81%); (iv) 10% Pd/C, EtOH/CH2Cl2, H2, rt, 3 h (yields 94−96%); (v) CH(OEt)3, PPTS,
xylenes, 140 °C, 3 h (yields 91−95%); (vi) bromoaryl, Pd(PPh3)2Cl2 or Pd(dppf)Cl2, CuI, Cs2CO3, dioxane, 110 °C, 12 h (yields 7−40%) or
bromoaryl, Pd(OAc)2, N-Xantphos, 1 M LiHMDS, DME, 85 °C, 1 h, for 14a, 15 (yields 22 and 12%, respectively) or chloroaryl, In(OTf)3,
dioxane, 100 °C, 24 h, (yield 26%); (vii) (1) ArCOCl, xylenes, 155 °C, 1 h; (2) MsOH, 155 °C, 2−3 h (yields 12−81%).
mid’s main metabolic pathway),15 which is further supported
by reduction in ezutromid’s exposure after repeated dosing in
both healthy volunteers and DMD patients.11−13
pyridyl equivalents were synthesized as they are predicted to
have lower lipophilicity than 2.27
To access the phosphinate esters of the benzo[d]oxazoles,
two main synthetic routes were devised (Scheme 1). In
General Route 1, the phosphinate esters were synthesized first,
followed by cyclization to the benzoxazole, and finally
attachment of the C(2)-aryl via C−H activation. Bromo 2-
nitrophenols were O-benzylated (4−5) and substituted with
phosphinic acid (6−7), and the resulting acids were esterified
to their corresponding ethyl phosphinate esters (8−9).
Subsequent hydrogenation led to 2-aminophenols 10 and 11
in a one-step reduction/deprotection, which in turn gave the
benzo[d]oxazoles 12 and 13 in a reaction with diethoxyme-
thoxyethane in the presence of PPTS. The final products (14−
27) were obtained with C−H activation using Pd(PPh3)2Cl2 or
Pd(dppf)Cl2 and CuI as catalysts. In another variation
Pd(OAc)2, Xantphos, and 1 M LiHMDS, in DME, were
used (14, 15). This led to hydrolysis of the ester in the case of
12, and the resulting phosphinic acid (14a) was reacted with
MeOH to give the final product 14.
A medicinal chemistry program was launched to improve
ezutromid’s suboptimal properties and led to a second
generation of utrophin modulators.16−18 Therein, a dual
strategy was implemented to improve solubility by replacement
of the sulfone moiety and to improve metabolic stability by
replacement of naphthalene with halo- and heteroaryls. A
promising lead molecule from this series (Figure 1,
SMT022357, 2) with an improved ADME profile increased
levels of utrophin protein in skeletal, respiratory, and cardiac
muscles, reduced regeneration, and improved muscle function
when administered orally to mdx mice.16 Further progression
of SMT022357 (2) was halted, due to dose-limiting
hepatotoxicity observed during subsequent maximum tolerated
dose studies in rats. A structurally similar, but less lipophilic,
analogue SMT022332 (Figure 1, (+)-enantiomer 3) was
instead progressed because of its encouraging activity and
efficacy in mdx mice and its improved safety profile.18
General route 2 was described in detail in our previous
work.18 In brief, intermediate 2-arylbromobenzo[d]oxazoles
(28−36) were derived from the condensation of 2-amino-
phenols with the respective acid chloride, followed by acid
catalyzed dehydration. The final products were obtained from
the bromobenzo[d]oxazoles in a Pd-catalyzed cross-coupling
with ethyl phosphinic acid (37−45) and were then converted
to the methyl phosphinate esters through formation of the
phosphinic chloride and reaction with MeOH (46−54).
Utrophin modulation activity was assessed using a reporter
gene assay in the previously reported cell line H2K-mdx utrnA-
luc (H2K), a murine myoblast cell line that contains a stably
integrated 8.4 kb fragment of the human utroA promoter
linked to a firefly luciferase gene.15,16,18 In the reporter gene
assay (Table 1), most of the o-substituted analogues appeared
to be inactive (18, 23, 50, 54); however, the o-difluoromethyl
During these studies, the relationship between lipophilicity
and hepatotoxicity within this compound series was inves-
tigated. Several empirical studies have correlated lipophilicity
with increased nonspecific binding and off-target effects, and a
decreased chance of clinical success.19,20 However, to our
knowledge, there are few published studies that directly
correlate lipophilicity with hepatotoxicity within a compound
series.21−25 Lipophilic compounds are more prone to extensive
metabolism and thus may result more frequently in drug-
induced liver injury (DILI).26 As we observed extensive
metabolism and in vivo hepatotoxicity in rodents with 2, which
translated in in vitro cellular hepatotoxicity for 2 and other
related examples,18 we felt that reducing lipophilicity would be
a good strategy for optimizing the series. To achieve this,
analogues that bear the -CHF2 and -OCHF2 groups and their
B
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Table 1. Structure Activity Relationships (SARs) of C2 (Hetero)aryl Analogues
a
b
Firefly luciferase reporter gene assay reported as EC50 SD (μM) of 3 biological replicates (3 technical replicates per experiment). Firefly
c
luciferase enzymatic assay reported as IC50 SD (μM) of 2 biological replicates (3 technical replicates per experiment). logD is calculated with
the shaking flask method at pH = 7.4 from the partition between n-octanol/water. Reference: Tetrahedron 2020, 76, 130819. IA, inactive. ND,
d
e
f
not determined.
analogues 14, 16, and 51 were active. Similarly, analogues
bearing the phosphinate ester substituent in position 6 were
inactive (23−27, 53−54), apart from the o- and p-
difluoromethyl analogues (51−52). Finally, pyridyl analogue
49 was also found to be inactive.
of recombinant Fluc enzyme activity in our screening workflow
allowed an early detection of compounds which exhibited
interference in the H2K reporter assay.
Interestingly, despite their structural similarity with
ezutromid,29 several of the new analogues showed little or
no inhibitory activity on Fluc (Table 1), with the exception of
methoxy analogues 17 and 47. Two difluoromethyl analogues
(14, 15) inhibited Fluc in the low micromolar range, and 19
was even less potent (IC50 of 23.6 μM). The previously
reported analogue 3 was found to inhibit Fluc with an IC50 in
the nanomolar range, while 2 was less potent with a low
micromolar IC50. None of the pyridyl-containing analogues
inhibited Fluc. Interestingly, we observed a trend that less
lipophilic compounds (logD7.4 < 2.5) showed reduced or no
activity in the Fluc assay, while several examples still showed
activity in the H2K reporter assay. This finding is consistent
In our previous work,18 confirmation of utrophin upregu-
lation activity with an orthogonal assay was accomplished with
labor-intensive Western blots. As we had previously demon-
strated that ezutromid is a noncompetitive inhibitor of the
firefly luciferase enzyme (Fluc),28 and recognizing the
complications Fluc inhibition can cause in the interpretation
of reporter gene assays,29 we sought a more facile counter-
screen to include in our assay cascade. Quantification of
utrophin protein using Western blots was still used for
confirmation of utrophin upregulation activity, but the
inclusion of a biochemical assay to directly measure inhibition
C
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with the work of others who have shown that this Fluc has a
preference for binding lipophilic molecules.30
Decreasing lipophilicity significantly improved aqueous
solubility, as was expected (Table 2). All the newly synthesized
inhibition, and optimal ADME properties. Analogue 52 was
selected as a representative haloaryl derivative, since it had a
well-balanced overall profile. All three analogues were found to
increase utrophin by approximately 1.3−1.6-fold (Figure 2).
Table 2. Structure Property Relationships (SPR) of the
Synthesized Analogues
c
Caco-2
A-B
mHep Stability
a
b
d
e
#
Sol
mPPB
B-A
Clint
T1/2
2
3
468
378
>250
>250
530
518
>250
366
576
733
477
440
469
574
834
603
487
265
97
95
97
94
98
97
96
97
98
86
75
74
97
98
93
80
77
18.0
18.0
16.2
14.2
16.4
15.7
11.2
10.1
11.9
9.12
>250
34.5
8.99
53.0
>250
>250
4.49
<2.89
<2.89
<2.89
18.2
58
76
<3
20
77
13
<3
<3
154
>240
>240
>240
38
154
>240
>240
>240
56
13
>240
4
<3
79
14
15
46
16
17
18
19
20
21
22
23
24
25
26
27
47
48
49
50
51
52
53
54
15.7
18.8
12.7
22.3
12.6
15.7
11.7
20.6
Figure 2. Treatment with 20, 21, and 52 increases utrophin protein in
LUmdx cells. *p < 0.05, **p < 0.01, ***p < 0.001. pos ctrl = positive
control.
12.3
17.2
21.8
11.5
16.2
16.9
4.49
<2.89
<2.89
<2.89
12.4
54.4
<2.89
184
>250
8.77
19.0
142
The modest increase in utrophin levels in combination with
the variability and low sensitivity of this assay are likely
responsible for the apparent lack of a dose−response; however,
these results demonstrate utrophin modulation in a cellular
context, confirming the activity in this series of new analogues.
In an attempt to visualize the move from a suboptimal
physicochemical property space, we plotted selected phys-
icochemical properties of the previously synthesized phosphi-
nate ester analogues against the new ones (Figure S1, Table
S1). At a glance, it was observed that the optimal chemical
space proposed by Gleeson (Figure S1a, gray area defined with
clogP < 4 and MW < 400)31 is mostly occupied by new
analogues. These “not large/not greasy” molecules were found
to have the best drug developability profiles according to a
separate analysis by Ritchie et al.32 Considering the more polar
nature of some of the analogues, we went on to experimentally
measure the logD of selected analogues and observed that
indeed they move almost entirely into the desired area (Figure
S1b).
The discovery that 2 was hepatotoxic during the maximum
tolerated dose study in rats,18 and the observation that 2 and
related compounds showed cytotoxicity in vitro in liver cells,
led us to probe the new analogues for their cytotoxic potential
in HepG2 cells (Table 3) as an early indication of
hepatotoxicity. Cytotoxicity was determined by quantification
of cellular ATP levels, using an evolved luciferase known to
have substantially reduced promiscuity.33 Increased lipophi-
licity has been known to contribute to compound promiscuity
and further toxicological outcomes.19,20,34,35 From the results
in Table 3 it was apparent that the most toxic compounds are
those with high lipophilicity and low TPSA, in good agreement
with other literature reports.19
13.3
13.3
12.3
10.7
9.37
11.0
854
446
556
8.4
699
89
97
96
96
76
18.1
15.9
37
5
a
b
Aqueous kinetic solubility (μM). mPPB, murine plasma protein
c
binding (% bound). Caco-2 permeability assay (Papp (10−6 cm/s)).
d
e
Murine hepatocyte intrinsic clearance (μL/min/106 cells). Murine
hepatocyte half-life (min).
analogues were equally or more water-soluble than 2 and 3.
The extent of plasma protein binding varied between different
analogues. Pyridyl derivatives were found to bind <90%, with
the exception of 25. All the new molecules were highly
permeable in Caco-2 cells, and more importantly no efflux was
noted for any of the new examples ([B-A]/[A-B] < 1). Finally,
the metabolic stability of the compounds was found to vary
considerably. Analogues 14, 16−18, 50, 51, and 54 were
cleared very quickly in mouse hepatocytes. Interestingly, most
of these analogues bear electron withdrawing groups in the
ortho position, which may suggest a potential opening of the
more electrophilic benzoxazole ring in these examples,
enabling further CYP oxidation. On the other hand, 20, 21,
25−27, and 49, m-substituted pyridyl analogues, were the most
metabolically robust. Apart from o-substituted analogues 50
and 54, all pyridyl analogues had improved metabolic stability
compared to their phenyl counterparts.
Next, we sought to quantify the relationship between
HepG2 cytotoxicity with key physicochemical properties. As
our sample size described herein was rather small, we also
expanded this analysis to include all synthesized compounds in
this series (Table S2, Figures 3 and S2).
Plotting pIC50 against TPSA did not give a statistically
significant correlation (data not shown); however, pIC50
Confirmation of utrophin modulation activity for represen-
tative analogues (20, 21, and 52) was determined using
Western blot to quantify the increase of the utrophin protein
levels in dystrophic mouse muscle cells (LUmdx), as before.18
Pyridyl analogues 20 and 21 were selected because of their
combination of potency in the H2K assay, lack of Fluc
D
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space and have better drug developability potential. The
decrease in lipophilicity gave inactive or only weakly active
analogues as Fluc inhibitors, while maintaining utrophin
modulatory activity. We were able to show that cytotoxicity
in HepG2 cells is directly proportional to lipophilicity and that
reducing lipophilicity led to analogues that were only mildly or
not cytotoxic at all in HepG2 cells.
Table 3. Cytotoxicity of Selected Compounds in HepG2
Cells
a
a
#
ClogP
TPSA
IC50 (μM)
2
4.43
3.68
3.10
5.35
3.51
3.48
5.19
4.96
5.30
62
62
84
81
71
75
62
62
62
58.4
200
200
68.9
200
200
0.02
13.3
5.04
b
3(e2)
20
24
47
49
55
56
57
ASSOCIATED CONTENT
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c
* Supporting Information
c
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acsmedchemlett.0c00405.
c
a
Generated with OSIRIS Datawarrior version 5.0.0 © 2002−2019
Experimental details describing the biological assays and
the synthesis and characterization of compounds.
Computational and experimental calculations of phys-
icochemical properties, graphs and equations. NMR and
mass spectroscopy spectra of the synthesized com-
pounds. (PDF)
Idorsia Pharmaceuticals Ltd. Cpd 27e2 in our previous work.18
b
c
Cpds 55−57 are reported in our previous work18 and are esters of 2
with isopropanol, cyclopropanol, and cyclobutanol, respectively.
against ClogP derived equation S1 (n = 14, R2 = 0.46, Figure
S2a). Examining the graph, we observed two compounds that
diverted from the group and considered removing them as
potential outliers. Indeed, after removal of the two, the
correlation between clogP and cytotoxicity appeared to
improve as shown in equation S2 (n = 12, R2 = 0.91, Figure 3).
AUTHOR INFORMATION
■
Corresponding Author
Angela J. Russell − Department of Chemistry, University of
Oxford, Chemistry Research Laboratory, Oxford OX1 3TA,
U.K.; Department of Pharmacology, University of Oxford,
Oxford OX1 3PQ, U.K.; orcid.org/0000-0003-3610-9369;
Email: angela.russell@chem.ox.ac.uk
Authors
Maria Chatzopoulou − Department of Chemistry, University of
Oxford, Chemistry Research Laboratory, Oxford OX1 3TA,
U.K.; orcid.org/0000-0003-1886-7705
Enrico Emer − Department of Chemistry, University of Oxford,
Chemistry Research Laboratory, Oxford OX1 3TA, U.K.
Cristina Lecci − Evoetec (U.K.) Ltd, Abingdon OX14 4RZ,
U.K.
Jessica A. Rowley − Department of Chemistry, University of
Oxford, Chemistry Research Laboratory, Oxford OX1 3TA,
U.K.
Anne-Sophie Casagrande − Evotec (France) SAS, 31100
Toulouse, France
Figure 3. Correlation between cytotoxicity in HepG2 cells and
lipophilicity as expressed from their pIC50 and clogP plot after the
removal of two outliers (n = 12). Predicted clogP (a) was generated
with OSIRIS Datawarrior version 5.0.0 © 2002−2019 Idorsia
Pharmaceuticals Ltd.
Lee Moir − MDUK Oxford Neuromuscular Centre, Department
of Physiology, Anatomy and Genetics, University of Oxford,
Oxford OX1 3PT, U.K.
Sarah E. Squire − MDUK Oxford Neuromuscular Centre,
Department of Physiology, Anatomy and Genetics, University of
Oxford, Oxford OX1 3PT, U.K.
Stephen G. Davies − Department of Chemistry, University of
Oxford, Chemistry Research Laboratory, Oxford OX1 3TA,
U.K.; orcid.org/0000-0003-3181-8748
Shawn Harriman − Summit Therapeutics plc, Oxfordshire
OX14 4SB, U.K.
Graham M. Wynne − Department of Chemistry, University of
Oxford, Chemistry Research Laboratory, Oxford OX1 3TA,
U.K.
The aberrant behavior of the two outliers may partly be
explained by gaps in the ability of software to predict clogP
successfully. Analogue 24 was predicted to be the most
lipophilic compound with Datawarrior; however, it was almost
one log unit less polar by the two other calculators (Table S3).
Similarly, analogue 55 was significantly more lipophilic when
other calculators were used. However, this analysis does not
rule out the participation of other mechanisms contributing to
the significantly higher cytotoxicity of this compound in
HepG2 cells. Importantly utrophin modulation activity in H2K
cells did not increase with clogP; plotting the ratio of EC50 in
H2K cells and the IC50 in HepG2 cells showed only a weak but
negative correlation (Table S2, Figure S2).
Aiming to improve the ADMET profile of existing
benzo[d]oxazole phosphinate utrophin modulators, we im-
plemented a strategy of reducing lipophilicity in the design of
new analogues. A facile synthetic route was devised that allows
faster access to analogues involving C−H activation of the
intermediate benzoxazole phosphinate ester. The new
analogues were shown to be in a more optimal chemical
Francis X. Wilson − Summit Therapeutics plc, Oxfordshire
OX14 4SB, U.K.
Kay E. Davies − MDUK Oxford Neuromuscular Centre,
Department of Physiology, Anatomy and Genetics, University of
Oxford, Oxford OX1 3PT, U.K.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acsmedchemlett.0c00405
E
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Johnson, P. D.; Lambert, A. G.; Lawrence, D.; Lecci, C.; Maillol, C.;
Middleton, P. J.; Nugent, G.; Poignant, S. D.; Potter, A. C.; Price, P.
D.; Pye, R. J.; Storer, R.; Tinsley, J. M.; van Well, R.; Vickers, R.; Vile,
J.; Wilkes, F. J.; Wilson, F. X.; Wren, S. P.; Wynne, G. M. Discovery of
2-arylbenzoxazoles as upregulators of utrophin production for the
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(10) Tinsley, J. M.; Fairclough, R. J.; Storer, R.; Wilkes, F. J.; Potter,
A. C.; Squire, S. E.; Powell, D. S.; Cozzoli, A.; Capogrosso, R. F.;
Lambert, A.; Wilson, F. X.; Wren, S. P.; De Luca, A.; Davies, K. E.
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upregulator, dramatically reduces the dystrophic symptoms in the
mdx mouse. PLoS One 2011, 6 (5), No. e19189.
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(12) Ricotti, V.; Spinty, S.; Roper, H.; Hughes, I.; Tejura, B.;
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azole utrophin modulator, following single- and multiple-dose
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Author Contributions
M.C. and A.J.R. collated the data and wrote the manuscript. All
authors have given approval to the final version of the
manuscript.
Funding
The authors wish to thank Summit Therapeutics plc (M.C.,
E.E., J.A.R, L.M.) and the Medical Research Council
(1501AV003/CA2, K.E.D., S.E.S.) for financial support.
Notes
The authors declare the following competing financial
interest(s): S.H. and F.X.W. are or were Summit Therapeutics
plc employees or consultants at the time that the work was
conducted. K.E.D., S.G.D. and A.J.R. are minor shareholders of
Summit Therapeutics plc.
ACKNOWLEDGMENTS
■
The authors kindly acknowledge Evotec (UK) for the
physicochemical and ADME characterization and Evotec
(France) for the biological evaluation. We further acknowledge
G.E. Morris (Oswestry, UK) for the MANCHO3 antibody.
ABBREVIATIONS
■
ADMET, administration distribution metabolism excretion
toxicity; CYP, cytochrome P450; DAPC, dystrophin associated
complex; DIPEA, N,N-diisopropylethylamine; DMAP, 4-
dimethylaminopyridine; DMD, Duchenne muscular dystro-
phy; DME, dimethoxyethane; dppf, 1,1′-bis-
(diphenylphosphino)ferrocene; Fluc, firefly luciferase; H2K,
reporter cell line H2K-mdx utrnA-luc; HMDS, hexamethyldi-
silazane; LUmdx, dystrophic mouse cells; PPB, plasma protein
binding; PPTS, pyridinium p-toluenesulfonate; SAR, struc-
ture−activity relationship; SPR, structure−property relation-
ship; TPSA, topological polar surface area.
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