Preclinical characterization of acyl sulfonimidamides: Potential carboxylic acid bioisosteres with tunable properties

Article abstract of DOI:10.1002/cmdc.201402497

Herein we present the preclinical characterization of novel compounds containing the linear acyl sulfonimidamide functionality. Specifically, we studied the pK_a, lipophilicity, in vitro metabolic stability, plasma protein binding, Caco-2 permea

Full text of DOI:10.1002/cmdc.201402497

DOI: 10.1002/cmdc.201402497
Communications
Preclinical Characterization of Acyl Sulfonimidamides:
Potential Carboxylic Acid Bioisosteres with Tunable
Properties
Sanjay R. Borhade,[a] Richard Svensson,[b, c] Peter Brandt,[a] Per Artursson,[b, c]
Per I. Arvidsson,*[c, d] and Anja Sandstrçm*[a]
Herein we present the preclinical characterization of novel
compounds containing the linear acyl sulfonimidamide func-
tionality. Specifically, we studied the pKa, lipophilicity, in vitro
metabolic stability, plasma protein binding, Caco-2 permeabili-
ty, and aqueous solubility for nine aryl acyl sulfonimidamides.
In comparison with widely used carboxylic acid bioisosteres,
the acyl sulfonimidamides were found to be less acidic and
more lipophilic depending on the substitution pattern in the
studied compounds. Importantly, the pKa values (5.9–7.6) were
significantly influenced by substituents on the nitrogen atom
and the aryl substituents. Moreover, the acyl sulfonimidamides
displayed membrane permeabilities ranging from moderate to
very high, which correlated with decreased pKa and low to
negligible efflux ratios. We foresee that the chiral sulfur center
and the two handles for structural diversity of linear acyl sulfo-
nimidamides will offer new opportunities for drug design and
for improving the oral bioavailability of acidic drug candidates.
reactions into reactive and toxic acyl glucuronides or CoA
esters, and can also be associated with extensive efflux; alto-
gether these factors can complicate drug therapies.[1–4] Given
these concerns, carboxylic acid bioisosteres, such as structures
2–7 in Figure 1, are commonly used as carboxylic acid replace-
ments in drug discovery.[1] For example, Davioud-Charvet and
co-workers showed that 5-substituted tetrazoles 2 can serve as
carboxylic acid bioisosteres in antimalarial glutathione reduc-
tase inhibitors with improved cell permeability.[5] Bioisosteres
are defined as groups or molecules that have similar physio-
chemical properties and that broadly elicit the same biological
activity for a particular target.[6]
Until recently, isosteric replacements of sulfone derivatives
8–10 have been less explored by medicinal chemists. Nonethe-
less, a bioactive pan-CDK inhibitor (BAY1000394) has entered
phase I studies and contains a sulfoximine (11) as an isostere
to a sulfone.[7] Furthermore, the research group of Bolm has re-
ported several bioactive sulfoximines with potent COX inhibi-
tory activity, antiproliferative activity, cellular toxicity, and mu-
tagenicity.[8–10] However, isosteric replacement in which the
sulfur-bonded oxygen atom of sulfonamides (9) and acyl sulfo-
namides (4) is replaced by a nitrogen atom, that is, to respec-
tively yield sulfonimidamides (12) and acyl sulfonimidamides
(14), have been only sparsely applied in the area of drug
design. For example, in the last decade, the research groups of
Dodd and Malarcia have used sulfonimidamide-containing sub-
stances in organic synthesis,[11–16] and a few reports, including
patent applications, have indicated the utility of the sulfonimi-
damide functional group in bioactive molecules.[17,18] However,
sulfonimidamide analogues (13, pKa ~9–11) of oncolytic diary-
lsulfonyl ureas (10, pKa ~5–7) synthesized by Toth et al. and
showed excellent growth inhibitory activity in evaluations for
in vitro cytotoxicity and in vivo antitumor activity.[19] Addition-
ally, we previously reported the successful use of sulfonimida-
mides, that is, 12, as potential bioisosteres of sulfonamides 9,
as well as their chiral separation.[20] Given the recent increased
interest in sulfone isosteres, we became interested in exploring
linear acyl sulfonimidamides (e.g., 14 and 15) as carboxylic
acid bioisosteres, and as alternatives to acyl sulfonamides (4),
in our medicinal chemistry program.[21–24] We anticipated that
acyl sulfonimidamides (such as 14) would be acidic entities,
and that the presence of the stereogenic tetrahedral sulfur
center combined with the additional points of diversity offered
by the imine nitrogen atom would make this functionality an
attractive carboxylic acid isosteric replacement in drug design
(Figure 1). Indeed, Pemberton et al. recently showed that two
The presence of a carboxylic acid functionality (i.e., 1) in a lead
molecule is often associated with poor absorption, distribution,
metabolism, elimination, and toxicity (ADMET) properties. In
particular, the high polarity of carboxylates is incompatible
with good absorption through lipid membranes, such as the
intestine and the blood–brain barrier. The carboxylic acid func-
tion can furthermore be metabolized by phase II conjugation
[a] Dr. S. R. Borhade, Dr. P. Brandt, Dr. A. Sandstrçm
Department of Medicinal Chemistry, Division of Organic Pharmaceutical
Chemistry, Biomedical Center, Uppsala University
P.O. Box 574, 751 23 Uppsala (Sweden)
E-mail: Anja.Sandstrom@orgfarm.uu.se
[b] Dr. R. Svensson, Prof. Dr. P. Artursson
Uppsala University Drug Optimization and Pharmaceutical Profiling
Platform (UDOPP) — a Node of the Chemical Biology Consortium Sweden
Department of Pharmacy, Biomedical Center, Uppsala University
P.O. Box 591, 751 24 Uppsala (Sweden)
[c] Dr. R. Svensson, Prof. Dr. P. Artursson, Prof. Dr. P. I. Arvidsson
Science for Life Laboratory (SciLifeLab), Drug Discovery & Development
Platform, and Division of Translational Medicine and Chemical Biology
Department of Medical Biochemistry and Biophysics
Karolinska Institute, Stockholm, Sweden
E-mail: per.arvidsson@scilifelab.se
[d] Prof. Dr. P. I. Arvidsson
Catalysis and Peptide Research Unit, School of Health Sciences
University of KwaZulu-Natal, Durban 4001 (South Africa)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cmdc.201402497: experimental details of syn-
1
theses, in vitro ADME profiling, and H and 13C NMR spectra.
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ously developed synthetic proto-
col.[28] The compounds were de-
signed to allow evaluation of the
acidic functionality per se; there-
fore, we deliberately chose to
avoid making an acyl sulfonimi-
damide analogue of a known
acid drug, as the success of a bio-
isostere replacement is critically
dependent on the biological sit-
uation at hand. We also studied
the potential influence of acyla-
tion of the second nitrogen
atom and the effect of various
substituents on the aryl groups.
The syntheses of N-acyl-N’-carba-
moyl (16 and 17) and N,N’-diacyl
sulfonimidamides (18) were ac-
complished by palladium-cata-
lyzed carbonylation using ex situ
generation of CO from Mo(CO)6
as a solid source in a sealed two-
chamber system, as outlined in
Scheme 1.[28]
Figure 1. Carboxylic acid 1 and examples of carboxylic acid bioisosteres 2–7. Sulfone containing derivatives 8–10
and bioisosteres 11–13. Proposed carboxylic acid bioisosteres, that is, the linear acyl and diacyl sulfonimidamides
14 and 15.
cyclic analogues of the related acyl sulfonimidamide function-
ality, that is, 7 vs. 14, possess promising physicochemical prop-
erties, including a slightly acidic proton, that allowed com-
pounds such as 7 to serve as a carboxylic acid bioisostere.[25]
Our proposed linear analogue offers an additional opportunity
to form diacylated compounds (such as 15), which we antici-
pate will increase acidity. Thus, the linear molecular scaffold
Scheme 1. Synthesis of N-acyl-N’-carbamoyl and N,N’-diacyl sulfonimida-
mides. Reagents and conditions: a) Pd(OAc)2 (10 mol%), Et3N (2.5 equiv),
Mo(CO)6 (1.5 equiv), DBU (2.0 equiv), 1,4-dioxane, 808C, 2 h.
can be extended in two directions beyond the “terminal posi-
tion” of a carboxylic acid and commonly used carboxylic acid
bioisosteres. Furthermore, the chirality of the sulfur center
offers opportunities to exploit enantiomeric differences in drug
optimization, in regard to both pharmacodynamic and phar-
macokinetic properties. The development of the pure sulfoxide
enantiomer esomeprazole (Nexium), with improved dosing,
from the racemic omeprazole (Losec), is a successful exam-
ple.[26] Acyl sulfonimidamides can also be used as carboxylic
acid (Ar-CO-OH) mimics in both directions, that is, with the car-
bonyl first (Ar-CO-NH-SO(NR)-Ar) or the sulfur atom (Ar-SO(NR)-
NH-CO-Ar) first in analogy with acyl sulfonamides.[27]
To access the N-acyl sulfonimidamides 20–25 the corre-
sponding N-Boc-protected sulfonimidamides were first car-
bonylated using aryl iodides to deliver the Boc-protected
common intermediate(s) 19, which was used without purifica-
tion for further treatment with trifluoroacetic acid (TFA) in
CH2Cl2 to remove the Boc group, thereby forming N-acyl sulfo-
nimidamides 20–25 in 52–74% overall yields, as shown in
Scheme 2.
Herein we report the first investigations of the physicochem-
ical and in vitro ADME properties of linear acyl sulfonimida-
mides. More specifically, acidity (pKa), distribution coefficient
(logD7.4), aqueous solubility, Caco-2 monolayer permeability
(Papp), ABC-transporter-mediated efflux, microsomal metabo-
lism, and plasma protein binding (PPB) were examined and are
compared with properties of the corresponding carboxylic acid
and related bioisosteres, such as acyl sulfonamide and tetra-
zole.
N-acyl- (20–25), N-acyl-N’-carbamoyl- (16–17), and N,N’-
diacyl- (18) sulfonimidamides possess interesting structural fea-
tures, as they may undergo tautomerization, placing the acidic
proton on either of the two nitrogen atoms, and possibly on
the two oxygen atoms, as illustrated in Figure 2. We undertook
some initial density functional theory (DFT) calculations on this
tautomeric equilibrium (B3LYP/6-311+G** with a PBF solvent
model for water).[29] For the carbamate-protected compound
16, the tautomeric form in which the acidic hydrogen atom is
attached to the Boc-containing nitrogen (A) was found to be
more stable than tautomer B, in which the hydrogen is at-
tached to the other nitrogen atom, by 1.2 kcalmolꢀ1 (see Sup-
For this initial exploration of a new functionality we decided
to synthesize nine different aryl acyl sulfonimidamides (com-
pounds 16–24), straightforwardly accessed by using our previ-
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of the aryl ring with electron-do-
nating groups such as methoxy
(21, pKa: 7.6) increases the pKa
values, whereas electron-with-
drawing substituents lower the
pKa (22–25, pKa: 6.6–7.2). Thus,
disubstitution with electron-
withdrawing groups (24, pKa:
6.9; 25, pKa: 6.6) at the para po-
sition of each aryl ring lowered
the pKa values by ~0.5 log units.
To our surprise, and in conflict
with quantum chemical calcula-
tions (see pKa values in paren-
theses marked with footnote [i],
Table 1), initial measurements
using the UV-metric method
showed equal or higher pKa
values for the N-acyl-N’-carba-
moyl- and the N-diacyl sulfonimi-
damide compounds 16–18 rela-
tive to 20. The unexpectedly
high pKa value for compound 16
was shown, by further MS analy-
sis, to result from hydrolytic deg-
radation of 16 into compound
20 under acidic conditions. How-
ever, the measured logD7.4 to-
gether with the calculated logP
values of the N-acyl-N’-carbamo-
yl and N-diacyl compounds 17–
18 argued against the measured
Scheme 2. Synthesis of N-acyl sulfonimidamides. Reagents and conditions: a) Pd(OAc)2 (10 mol%), Et3N (2.5 equiv),
Mo(CO)6 (1.5 equiv), DBU (2.0 equiv), 1,4-dioxane, 808C, 2 h; b) TFA, CH2Cl2, RT, 3 h.
Figure 2. Calculated energies for the four possible tautomeric forms of acyl sulfonimidamide in water (20D opti-
mizes to 20C).
porting Information for details). This calculated marginal differ-
ence in relative energy is in line with both tautomers of carba-
mate-protected acyl sulfonimidamides being visible on the
NMR timescale (see Supporting Information). For the free acyl
sulfonimidamide 20, we found that tautomer A is more stable
by 2.4 kcalmolꢀ1 than tautomer B, which is in agreement with
related calculations for the cyclic analogue 7.[25] Clearly, the cal-
culations suggest that the imine prefers to be conjugated with
an acyl carbonyl, but also that protonation on the nitrogen
atoms is significantly more preferred over protonation of the
oxygen atoms (tautomers C and D).
Lipophilicity and acidity are important parameters in the
design of pharmaceutical agents and are known to influence
many key ADME properties of a drug, such as metabolic stabili-
ty, PPB, toxicity, and cell membrane permeability.[30] Thus, we
initially measured the lipophilicity at pH 7.4 (logD7.4) and acidi-
ty (pKa) of acyl sulfonimidamides 16–25 using a shake-flask oc-
tanol/phosphate buffer distribution method and a UV-metric
method (Sirius Analytical Ltd.), respectively. The results are
summarized in Table 1. Experimental pKa values for the select-
ed acyl sulfonimidamide compounds were initially found to be
in the range of 6.6–7.7 (by the UV-metric method), and logD7.4
values between 1.2 and 4.2 for the N-acyl sulfonimidamides
and ꢀ1.0 to 0.5 for the N-acyl-N’-carbamoyl- (16, 17) or the
N,N’-diacylated (18) sulfonimidamides. In general, substitution
pKa values. Estimating these pKa values from the experimental
logD7.4 and clogP values suggested pKa values more in the
range of 4.5–5.5 (see pKa values in parentheses marked with
footnote [h], Table 1) and that the acidity for the N-acyl-N’-car-
bamoyl- and N-diacyl sulfonimidamides 16–18 should be more
similar to carboxylic acids and its common bioisosteres. This
encouraged us to challenge the UV-metric method with the
more direct potentiometric method, using the same equip-
ment. The potentiometric method requires approximately ten-
fold higher concentrations and necessitated the use of co-sol-
vent (methanol) in the titrations to prevent precipitation at
low pH. This method clearly indicated lower pKa values (~5.9)
for 17 and 18, but additional electron-withdrawing functions
(ethyl vs. phenyl) beyond the carbonyl had a smaller effect. To
validate the pKa values obtained with the UV-metric method
and the potentiometric method with co-solvent, compounds
20–23 and 26 were re-evaluated with relatively good correla-
tion (Table 1). The reason why compounds 17 and 18 failed to
give an accurate pKa with the UV-metric method is, however,
currently unknown.
Kinetic solubility was determined in phosphate-buffered
saline (PBS) at pH 7.4 with a final DMSO concentration of 1%.
All the compounds were moderately (>10 mm) to highly (ꢁ
100 mm) soluble at this pH, with solubilities ranging between
25 and 100 mm (Table 1). In analogy with the highest clogP
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Table 1. In vitro physiochemical and pharmacokinetic properties of investigated compounds.
Compound
pKa[a]
UV/(Pred.)
clogP
logD7.4
Sol. [mm][b]
PPBfu [%][c]
Papp (a!b)ꢁ10ꢀ6 cmsꢀ1[d]
Efflux[e]
t1/2 [min][f]
Pot.
7.38[g]
(4.3)[h]
(5.0)[i]
ND[j]
3.6
2.9
0.5
ꢁ100
0.4
1.0
ND
0.3
ND
2.1
>40
>40
7.41
(3.5)[h]
5.92
ꢀ1.0
65
7.76
(4.5)[h]
5.86
7.55
3.4
1.9
0.5
1.2
82
92
0.5
4.7
ND
ND
0.5
>40
>40
7.38
(6.8)[h]
(7.1)[i]
261
7.61
7.17
7.02
6.92
6.62
7.30
7.06
6.79
2.2
3.0
2.0
3.6
1.6
2.9
1.6
4.1
63
ꢁ100
69
0.8
0.4
1.2
0.1
ND
150
ND
ND
ND
0.82
ND
ND
>40
>40
>40
>40
ND
60
ND
4.0
2.1
4.2
25
91
0.1
3.6
38
2
1.89
0.90
>40
>40
3.33
(4.0)[h]
3.96
ꢀ1.3
3.96
4.20
ND
ND
1.8
1.1
ꢀ1.5
ꢀ1.0
ND
ND
ND
2.1
ND
ND
ND
ND
ND
>40
[a] pKa values were determined by UV and/or a potentiometric (Pot.) method. [b] Aqueous solubility was measured at pH 7.4. [c] PPB fraction unbound (fu)
in human plasma. [d] Caco-2 monolayer Papp coefficients were determined in both the apical (a) to basolateral (b) direction and the b!a direction.
[e] Efflux was determined as the (b!a)/(a!b) ratio. [f] Metabolic stability was measured over the course of 40 min in human liver microsomes (HLM) at
a concentration of 0.5 mgmLꢀ1 HLM. [g] Compound 16 is unstable and degraded to compound 20 during pKa measurements. [h] pKa value estimated from
experimental logD and clogP. [i] pKa value calculated by quantum chemical methods. [j] ND: not determined.
value of 4 and a measured logD value of 4.2, the CF3-substitut-
ed compound 25 was the least soluble (25 mm) amongst all
the studied compounds. However, the current assay setup pre-
vents any detailed conclusions to be drawn on how to distin-
guish the contribution of substituents or how charge affects
the solubility in this scaffold.
charge. In particular for acids, the negative charge is a major
determinant, and the results listed in Table 1 are no exception
to this rule.[31,32] The acyl sulfonimidamide 20 (fraction un-
bound (fu): 4.7%) and the acyl sulfonamide 26 (fu: 3.6%)
showed the least binding, and the other compounds (16–18
and 21–25) follow a trend toward higher binding in accord-
ance with increased lipophilicity and stronger acidity caused
by substitution on either the aryl ring or on the imine nitrogen
atom.
Human plasma protein binding was performed by rapid
equilibrium dialysis. The degree of plasma protein binding
(PPB) is typically determined by a compound’s lipophilicity and
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Isosteric replacement of carboxylic acids is often used to im-
prove membrane permeability, and this encouraged us to in-
vestigate and compare the permeability of compounds 17, 20,
22, and 25 with the corresponding acyl sulfonamide 26. The
most commonly used in vitro method to predict human intes-
tinal epithelial permeability is to measure transport rates
across Caco-2 cell monolayers as apparent permeability coeffi-
cients (Papp). In our calibrated assay setup, a Papp value below
0.2ꢁ10ꢀ6 cmsꢀ1 predicts low, 0.2ꢁ10ꢀ6 cmsꢀ1 to 1.6ꢁ
10ꢀ6 cmsꢀ1 moderate, and a Papp value above 1.6ꢁ10ꢀ6 cmsꢀ1
indicates high intestinal permeability. The evaluated substan-
ces did not affect the Caco-2 monolayer integrity, as evaluated
by trans-epithelial electrical resistance and mannitol permeabil-
ity—a paracellular monolayer integrity marker indicative of ap-
parent cytotoxicity. The data in Table 1 display a very wide
range in apical to basolateral (a!b) permeability for the se-
lected acyl sulfonimidamides (i.e., 17, 20, 22, and 25), from
0.3ꢁ10ꢀ6 to 261ꢁ10ꢀ6 cmsꢀ1. For passive permeability, these
results follow the theoretical degree of ionization fairly well.
Thus, passive permeability is determined by the concentration
of the neutral species, which is reduced with decreased pKa. In
opportunities for drug design and to improve oral bioavailabil-
ity of acidic drug candidates.
Author contributions
S.B. prepared all compounds and was responsible for execution,
R.S. and P.A. planned and R.S. performed the ADME experiments,
P.B. performed computational studies, P.I.A. and A.S. initiated and
designed the project. All co-authors contributed to interpretation
of the data and writing of the manuscript. All authors have given
approval to the final version of the manuscript.
Acknowledgements
The authors are grateful to the Chemical Biology Consortium
Sweden (CBCS) and the Erasmus-Mundus EXPERTS Foundation
for providing financial support. This work is based on the re-
search supported in part by the National Research Foundation of
South Africa (grant 87706).
Keywords: acidity · acyl sulfonimidamides · bioisosteres ·
lipophilicity · permeability
comparison with the matched-pair acyl sulfonamide 26 (Papp
2ꢁ10ꢀ6 cmsꢀ1), all acyl sulfonimidamides (e.g., 20, 22, and 25;
app =38–261ꢁ10ꢀ6 cmsꢀ1) except the diacylated compound
=
P
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Received: December 19, 2014
Revised: December 29, 2014
Published online on && &&, 0000
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COMMUNICATIONS
Carboxylic acid bioisosteres: A series
of linear acyl sulfonimidamides were
synthesized and evaluated for their in
vitro physicochemical and ADME prop-
erties such as pKa, lipophilicity, metabol-
ic stability, plasma protein binding,
Caco-2 permeability, and aqueous solu-
bility. These compounds are less acidic
than carboxylic acid and showed excel-
lent cell permeability, high solubility,
and minor intestinal efflux.
S. R. Borhade, R. Svensson, P. Brandt,
P. Artursson, P. I. Arvidsson,*
A. Sandstrçm*
&& – &&
Preclinical Characterization of Acyl
Sulfonimidamides: Potential
Carboxylic Acid Bioisosteres with
Tunable Properties
ChemMedChem 0000, 00, 0 – 0
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ꢀ 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
These are not the final page numbers! ÞÞ