Evaluation of Oxetan-3-ol, Thietan-3-ol, and Derivatives Thereof as Bioisosteres of the Carboxylic Acid Functional Group

Article abstract of DOI:10.1021/acsmedchemlett.7b00212

The oxetane ring serves as an isostere of the carbonyl moiety, suggesting that oxetan-3-ol may be considered as a potential surrogate of the carboxylic acid functional group. To investigate this structural unit, as well as thietan-3-ol and the corresponding sulfoxide and sulfone derivatives, as potential carboxylic acid bioisosteres, a set of model compounds has been designed, synthesized, and evaluated for physicochemical properties. Similar derivatives of the cyclooxygenase inhibitor, ibuprofen, were also synthesized and evaluated for inhibition of eicosanoid biosynthesis in vitro. Collectively, the data suggest that oxetan-3-ol, thietan-3-ol, and related structures hold promise as isosteric replacements of the carboxylic acid moiety.

Full text of DOI:10.1021/acsmedchemlett.7b00212

Subscriber access provided by Karolinska Institutet, University Library
Letter
Evaluation of Oxetan-3-ol, Thietan-3-ol and Derivatives Thereof
as Bio-isosteres of the Carboxylic Acid Functional Group
Pierrik Lassalas, Killian Oukoloff, Vishruti Makani, Michael James, Van Tran, Yuemang
Yao, Longchuan Huang, Krishna Vijayendran, Ludovica Monti, John Q Trojanowski, Virginia
M.-Y. Lee, Marisa C Kozlowski, Amos B Smith, III, Kurt R Brunden, and Carlo Ballatore
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.7b00212 • Publication Date (Web): 05 Jul 2017
Downloaded from http://pubs.acs.org on July 5, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
ACS Medicinal Chemistry Letters is published by the American Chemical Society. 1155
Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 5
ACS Medicinal Chemistry Letters
Evaluation of Oxetan-3-ol, Thietan-3-ol and Derivatives Thereof as
Bio-isosteres of the Carboxylic Acid Functional Group
Pierrik Lassalas,1 Killian Oukoloff,2 Vishruti Makani3, Michael James, 3 Van Tran,1 Yuemang Yao,3 Long-
chuan Huang,1 Krishna Vijayendran, 1 Ludovica Monti,2 John Q. Trojanowski,3 Virginia M.-Y. Lee,3 Mari-
sa C. Kozlowski,1 Amos B. Smith, III,1 Kurt R. Brunden,3 and Carlo Ballatore2
1
2
3
4
5
6
7
8
1Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA
19104; 2 Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego,
9500 Gilman Drive, La Jolla, CA 92093; 3 Center for Neurodegenerative Disease Research, Department
of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania,
Philadelphia, PA 19104.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
KEYWORDS: Oxetan-3-ol, thetan-3-ol, carboxylic acid bio-isostere, cyclooxygenase, lipoxygenase, dual inhibitors
ABSTRACT: The oxetane ring serves as an isostere of the carbonyl moiety, suggesting that the oxetan-3-ol may be considered as a
potential surrogate of the carboxylic acid functional group. To investigate this structural unit, as well as the thietan-3-ol and the
corresponding sulfoxide and sulfone derivatives, as potential carboxylic acid bio-isosteres, a set of model compounds has been
designed, synthesized and evaluated for physicochemical properties. Similar derivatives of the cyclooxygenase inhibitor, ibu-
profen, were also synthesized and evaluated for inhibition of eicosanoid biosynthesis in vitro. Collectively, the data suggest that
the oxetan-3-ol, thietan-3-ol and related structures hold promise as isosteric replacements of the carboxylic acid moiety.
evaluated a focused set of derivatives of the phenylpropionic
acid (1, Table 1), as this carboxylic acid was already employed as
The (bio)-isosteric replacement of the carboxylic acid moiety of
biologically active compounds is a common strategy in medicinal
a template structure in the synthesis and evaluation of a series of
chemistry that is frequently employed to improve/modify the
analogs comprising a wide selection of known carboxylic acid
surrogates.20 The properties evaluated here include acidity (pKa),
pharmacokinetic and/or pharmacodynamic properties of com-
pounds of interest.1-3 Although carboxylic acid isosteres are typi-
lipophilicity (logD7.4), and permeability in the Parallel Artificial
cally designed to mimic the carboxylic acid functional group, it is
Membrane Permeability Assay (PAMPA). Hydrogen-bonding
often the difference in structure and physicochemical properties
studies were also conducted to evaluate these fragments as hy-
of the isosteric replacement relative to the carboxylic acid that is
drogen bond (HB) donors. In addition, to evaluate the potential
critical to the success of this strategy. For this reason, and in
of the oxetan-3-ol, the thietan-3-ol and related sulfoxide and
consideration of the fact that the success of any isosteric re-
sulfone derivatives as replacements of the carboxylic acid moiety
placement is typically context dependent, the evaluation and
development of alternative surrogate structures that could com-
in the context of biologically active compounds, a small set of
derivatives of the cyclooxygenase (COX) inhibitor, ibuprofen (2,
Table 2), were designed, synthesized and evaluated as inhibitors
of eicosanoid formation in rat basophilic leukemia (RBL-1) cells.
plement and expand the existing set of bio-isosteres continues to
be a promising area of research.4-9
In recent years the oxetane ring has attracted considerable at-
tention in medicinal chemistry10 due to the fact that this four-
membered ring heterocycle can be used to modulate important
physicochemical properties of molecules, including aqueous sol-
ubility,11 lipophilicity, and metabolic stability.12 A series of publi-
cations12-15 illustrated the potential of the oxetane ring as an
isosteric replacement of the gem-dimethyl and the carbonyl
group (Figure 1A&B). Importantly, 3-substituted oxetanes have
been proposed as potential replacements of carboxylic esters
and amides (Figure 1C&D).14, 16-19 These findings indicate that the
oxetan-3-ol could be a potentially promising replacement of the
carboxylic acid. Thus far, however, an evaluation of this fragment
as a carboxylic acid surrogate has not been reported (Figure 1E).
Figure 1. The oxetane ring holds promise as an isosteric replace-
ment of the gem-dimethyl (A), and the carbonyl group in the
context of ketones (B), esters (C), and amides (D); similar re-
placements may be of interest in the context of carboxylic acids
(E).
Given our ongoing interest in the area of carboxylic acid bio-
isosteres,6-8, 20, 21 we set out to investigate a range of physico-
chemical properties of the oxetan-3-ol, as well as the thietan-3-ol
and the corresponding sulfoxide and sulfone structural units. To
enable a more informative and rigorous comparison of the prop-
erties of these fragments relative to those of carboxylic acids and
other known carboxylic acid bio-isosteres, we constructed and
Collectively, the data generated from these studies provide a
characterization of a range of physicochemical properties of ox-
ACS Paragon Plus Environment

ACS Medicinal Chemistry Letters
Page 2 of 5
etan-3-ol, thietan-3-ol and related structures, and in turn exem-
1
2
plify the possible utility of these fragments as replacements of
the carboxylic acid functional group in drug design.
3
4
5
Table 1. Calculated and Experimental Properties of Test Compounds.
6
7
8
9
PAMPA
logD7.4
pKa
H bonding
ln(Keq)g
a
f
Cpd #
1
Structure
logD7.4
pKa
calc.b
calc.b
e
Pe (cm/s)c
% retentiond
logPapp
–0.49
1.66E–06
± 3.48E–7*
–5.79
–0.56*
–6.8 ± 11*
–11.9%
11.4%
10.0%
10.7%
ND
4.64*
>12
>12
>12
9.31
ND
4.7*
13.5
14.3
14.2
13.6
15.4
4.31*
2.53
2.40
3.46
3.76
± 0.19*
± 0.10*
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
4
2.07
2.99
1.22
1.24
ND
1.7
8.27E–06
1.32E–05
6.23E–06
1.22E–05
ND
–5.08
2.28
0.48
0.58
2.64
–4.88
–5.21
–4.91
ND
5
6
16
1.62
a Distribution coefficient between n-octanol and aqueous buffer (pH 7.4) determined by LC/MS (experiment run by WuXi AppTech); Cal-
culated values using ChemAxon; Effective permeability (PAMPA assay run by Analyza); Membrane retention; Log of the apparent
permeability coefficient; pKa values determined by capillary electrophoresis (experiment run by Analyza); ln of the equilibrium con-
stants (Keq) determined from a colorimetric assay that monitors the blue-shift of the maximum wavelength of a fluorescent pyrazinone
HB acceptor upon complexation with the HB donor analyte; * data previously reported;20 ND = not determined
b
c
d
e
f
g
The synthesis of oxetane and thietane derivatives 3–6 and 7–10
was conducted as highlighted in Scheme 1. Model compounds
3–6 were constructed starting from phenethylmagnesium bro-
mide 11 and the appropriate oxetan-3-one (12) or thietan-3-one
(13) to give alcohols 3 and 4, respectively. Treatment of the
thietan-3-ol derivative 4 with urea-hydrogen peroxide complex
(UHP) in acetic acid led to the corresponding sulfoxide as a mix-
fact that sulfone derivative 6 exhibits a pKa value of ~9.3, while
all other derivatives were found to have pKa values >12 (i.e.,
above the range of the assay), with calculated values as high as
~14. However, an evaluation of the hydrogen bond (HB) acidity
of these compounds, which was conducted employing a previ-
ously reported colorimetric assay,22 suggested that these re-
placements cause a far less dramatic reduction in the HB acidity
scale relative to 1. For example, compound 3 exhibited at least
eight orders of magnitude lower acidity relative to 1, but less
than two orders of magnitude weaker binding via hydrogen
bonding to the fluorescent HB acceptor used in the assay (see
equilibrium constant, Keq, values of test compounds 3–6, Table
1). Also of interest, the Keq values of 3–6 are significantly higher
than that of alcohol 16, confirming that the four-membered ring
heterocycles found in compounds 3–6 play an important role in
determining the HB-donating ability of the hydroxyl moiety.
These observations, combined with prior studies that estab-
lished the remarkable HB basicity of the oxetane ring,23 suggest
that the oxetan-3-ol 3 and related structures 4–6 have signifi-
cant HB capacity.
1
ture (6:4) of cis- and trans-isomers, as determined by H NMR.
When m-CPBA was used for the oxidation step, the cis/trans
ratio was > 98:2. Recrystallization of this mixture led to the for-
mation of crystals of the cis-isomer 5 that were suitable for X-ray
diffraction analysis (Scheme 1). Alternatively, oxidation of 4 with
2.2 equiv. of Oxone® led to the formation of the fully oxidized
sulfone derivative 6, a crystalline material that enabled X-ray
diffraction analysis (see Supporting Information). In a similar
fashion, the synthesis of ibuprofen derivatives 7–10 was carried
out starting from known alkyl chloride 14, which was prepared in
two steps from commercially available ketone 15. Grignard addi-
tion to 12 or 13 yielded the oxetan-3-ol derivative 7 and thietan-
3-ol derivative 8, respectively. Oxidation of the latter compound
with m-CPBA led to the sulfoxide derivative 9 (cis/trans ratio >
20:1), while oxidation of 8 with Oxone® (2.2 equiv) resulted in
sulfone derivative 10.
Evaluation of physicochemical properties of model compounds
3–6 revealed that replacement of the carboxylic acid of 1 with
these four-membered ring heterocycles results in a drastic re-
duction in acidic character (see Table 1). This is evident from the
2
ACS Paragon Plus Environment

Page 3 of 5
ACS Medicinal Chemistry Letters
X
Cpd
PGE2/D2
Assay IC50 (μM)a
LTB4 Assay
IC50 (μM)b
X
MgCl
a
OH
1
2
3
4
5
6
7
8
9
10
+
O
11
X = O (3)
X = S (4)
X = SO (5)
X = SO2 (6)
X = O (12)
X = S (13)
b or c
c
X-ray structure of 5
2
0.6 (0.3–1.1)*
>100
>100
OH
17
X
O
Cl
31.8 (24.6–41.0)*
d, e
f
15
14
R = Me X = O (7)
R = Me X = S (8)
R = Me X = SO (9)
R = Me X = SO2 (10)
c
g
18
28.1 (10.6–74.5)*
>100
Scheme 1. Reagents and Reaction conditions: a) THF, –78 °C,
15 min, then rt, 1 h; b) UHP, AcOH, rt, 14 h; c) m-CPBA, CH2Cl2, –
78 °C, 1 h; d) NaBH4, MeOH, 0 °C to rt, 30 min; e) SOCl2, CH2Cl2,
0 °C to rt, 18 h; f) (i) Mg, LiCl, ZnCl2, THF, rt, 6 h, (ii) 12 or 13, THF,
rt, 17 h; g) Oxone®, acetone/H2O, 0 °C to rt, 20 h
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7
8
9
34.1 (25.9–44.9)*
>100
8.4 (6.4–10.9)*
7.6 (4.9–11.8)*
11.7 (6.2–22.4)*
The combination of limited acid character with the ability to
establish HB may be a desirable feature of these structural units
with respect to possible applications in drug design, especially in
those circumstances where the presence of a negatively ioniza-
ble acid in a drug candidate may be responsible for an insuffi-
cient passive diffusion across biological membranes. Indeed,
consistent with the relatively high pKa values and with these
molecules being mostly neutral at physiological pH, all of the
model compounds were found to be comparatively more lipo-
philic and permeable in the PAMPA assay compared to 1. Fur-
thermore, a comparison of physicochemical properties of model
compounds 3–6 with 33 other phenylpropionic acid derivatives
in which the carboxylic acid moiety was replaced by known car-
boxylic acid surrogates reveals that the four-membered ring
heterocycles 3–6 are amongst the most permeable derivatives
within the entire set (see supplemental Figure 1, Supporting
Information).
17.4 (5.7–53.5)*
10
14.6 (12.1–17.5)*
20.2 (16.0–
25.4)*
a
Inhibition of COX pathway as determined by LC/MS/MS
analyses of the combined production of COX-derived PGD2 and
PGE2 in RBL-1 cells upon stimulation with arachidonic acid in the
presence or absence of test compounds; Inhibition of 5-LOX
pathway as determined by LC/MS/MS analyses of the produc-
tion of 5-LOX-derived LTB4 in RBL-1 cells upon stimulation with
arachidonic acid in the presence or absence of test compounds;
* The data represent the calculated IC50 values and associated
95% confidence intervals as determined from triplicate samples
at each concentration after a sigmoidal curve fit using GraphPad
Prism software.
b
Evaluation of ibuprofen derivatives was conducted employing a
modified RBL-1 cell assay that was previously developed for the
evaluation of 5-lipoxygenase (5-LOX) inhibition,24 and which we
adapted to monitor for compound inhibition of both COX and 5-
LOX biosynthetic pathways. In addition to oxetane and thietane
derivatives (7–10), ibuprofen analogs bearing a tetrazole25 (17)
and a cyclopentane-1,3-dione (18) were also constructed and
tested for comparison. Typical assay conditions involved the co-
incubation of RBL-1 cells in 24-well plates with different concen-
trations of test compounds for 2 h, followed by the addition of
the calcium ionophore, A23187 (12 μM), for 15 min to induce
arachidonic acid production. Culture supernatants were subse-
quently collected and assessed for COX-derived prostaglandins
(PGs) and 5-LOX-derived leukotrienes (LTs) by LC-MS/MS, as
described in Supporting Information. In initial concentration-
response testing (Table 2), LTB4, as well as combined PGD2 and
PGE2, which co-eluted under the chromatographic conditions,
were quantified. In subsequent studies, a refined LC-MS/MS
protocol was employed that permitted separate analyses of
PGD2 and PGE2, as well as LTB4 and LTC4 (see Supporting Infor-
mation).
Interestingly, the RBL-1 cell assay results revealed that replace-
ment of the carboxylic acid moiety of 2 with the comparatively
less acidic and more permeable four-membered ring structures
results in analogs (7–10) that, unlike 2 as well as the tetrazole
(17) and the cyclopentane-1,3-dione (18) derivatives, inhibit 5-
LOX-mediated synthesis of LTB4. Furthermore, with the excep-
tion of thietan-3-ol derivative 8, analogs 7, 9 and 10 were found
to inhibit the formation of both COX- and 5-LOX-derived eico-
sanoids with 9 and 10 exhibiting balanced inhibition activity in
the µM range (see Figure 2). Although the RBL-1 assay does not
permit us to unambiguously determine the enzymes in the ara-
chidonic acid cascade that are inhibited by the test compounds,
the observation that 7, 9 and 10 effectively reduce the formation
of multiple PGs and LTs (see supplemental Table 1, Supporting
Information) suggests that such inhibition is likely to take place
at the COX and 5-LOX enzymes. These findings appear to be
generally consistent with prior reports showing that selected
bio-isosteric replacements of the carboxylic acid moiety of dif-
Table 2. IC50 values of test compounds in the PGE2/PGD2 and
LTB4 assay.
3
ACS Paragon Plus Environment

ACS Medicinal Chemistry Letters
Page 4 of 5
ferent non-steroidal anti-inflammatory drugs (NSAIDs), including
ABBREVIATIONS
1
2
3
4
5
6
7
8
2, can result in inhibitors of the 5-LOX pathway or multi-targeted
derivatives capable of inhibiting concurrently multiple enzymes
in the COX- and 5-LOX biosynthetic pathways. 26, 27
PG, prostaglandin; LT, leukotriene; HB, hydrogen bond.
REFERENCES
1.
2.
3.
4.
Ballatore, C.; Huryn, D. M.; Smith, A. B., III, Carboxylic acid
(bio)isosteres in drug design. ChemMedChem 2013, 8,
385-395.
Meanwell, N. A. Synopsis of Some Recent Tactical
Application of Bioisosteres in Drug Design. J. Med. Chem.
2011, 54, 2529-2591.
Herr, R. J. 5-Substituted-1H-tetrazoles as carboxylic acid
isosteres: medicinal chemistry and synthetic methods.
Bioorg. Med. Chem. 2002, 10, 3379-93.
Duncton, M. A. J.; Murray, R. B.; Park, G.; Singh, R.
Tetrazolone as an acid bioisostere: application to
marketed drugs containing a carboxylic acid. Org. Biomol.
Chem. 2016, 14, 9343-9347.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5.
6.
Borhade, S. R.; Svensson, R.; Brandt, P.; Artursson, P.;
Arvidsson, P. I.; Sandstrom, A. Preclinical characterization
of acyl sulfonimidamides: potential carboxylic acid
bioisosteres with tunable properties. ChemMedChem
2015, 10, 455-60.
B Ballatore, C.; Soper, J. H.; Piscitelli, F.; James, M.; Huang,
L.; Atasoylu, O.; Huryn, D. M.; Trojanowski, J. Q.; Lee, V.
M.; Brunden, K. R.; Smith, A. B., III, Cyclopentane-1,3-
dione: a novel isostere for the carboxylic acid functional
group. application to the design of potent thromboxane
(A2) receptor antagonists. J. Med. Chem. 2011, 54, 6969-
6983.
Figure 2. Concentration-response analyses of inhibition of 5-
LOX-derived LTB4 and COX-derived PGE2/PGD2 by compounds 2
(top) and 10 (bottom). Error bars represent standard error of the
mean from triplicate samples.
Taken together, our results clearly suggest that the oxetan-3-ol
as well as the thietan-3-ol and related sulfoxide and sulfone
derivatives may be considered as alternative bio-isosteres of the
carboxylic acid functional group. Given the relatively low acidity
and high permeability, these fragments may be considered es-
pecially in the context of CNS drug design, when isosteric re-
placement of the carboxylic acid is often needed to improve the
brain penetration of a candidate compound.
7.
8.
Ballatore, C.; Gay, B.; Huang, L.; Robinson, K. H.; James, M.
J.; Trojanowski, J. Q.; Lee, V. M. Y.; Brunden, K. R.; Smith,
A. B., III, Evaluation of the cyclopentane-1,2-dione as a
potential bio-isostere of the carboxylic acid functional
group. Bioorg. Med. Chem. Lett. 2014, 24, 4171-4175.
Wang, X.; Liu, L.; Huang, L.; Herbst-Robinson, K.; Cornec,
A.-S.; James, M. J.; Sugiyama, S.; Bassetto, M.; Brancale,
A.; Trojanowski, J. Q.; Lee, V. M. Y.; Smith, A. B., III;
Brunden, K. R.; Ballatore, C. Potent, long-acting
cyclopentane-1,3-dione thromboxane (A2)-receptor
antagonists. ACS Med. Chem. Lett. 2014, 5, 1015-1020.
Pemberton, N.; Graden, H.; Evertsson, E.; Bratt, E.; Lepistö,
M.; Johannesson, P.; Svensson, P. H. Synthesis and
functionalization of cyclic sulfonimidamides: a novel chiral
heterocyclic carboxylic acid bioisostere. ACS Med. Chem.
Lett. 2012, 3, 574-578.
AUTHOR INFORMATION
Corresponding Author
9.
cballatore@ucsd.edu; kbrunden@upenn.edu
ASSOCIATED CONTENT
Supporting Information. Experimental details; NMR spectra of
test compounds; X-ray crystal structures; Supplemental Table 1;
Supplemental Figure 1; docking studies. This material is available
free of charge via the Internet at http://pubs.acs.org.
10. Bull, J. A.; Croft, R. A.; Davis, O. A.; Doran, R.; Morgan, K. F.
Oxetanes: recent advances in synthesis, reactivity, and
medicinal chemistry. Chem. Rev. 2016, 116, 12150-12233.
11. Skoda, E. M.; Sacher, J. R.; Kazancioglu, M. Z.; Saha, J.;
Wipf, P. An uncharged oxetanyl sulfoxide as a covalent
modifier for improving aqueous solubility. ACS Med.
Chem. Lett. 2014, 5, 900-904.
12. Wuitschik, G.; Rogers-Evans, M.; Müller, K.; Fischer, H.;
Wagner, B.; Schuler, F.; Polonchuk, L.; Carreira, E. M.
Oxetanes as promising modules in drug discovery. Angew.
Chem. Int. Ed. 2006, 45, 7736-9.
Author Contributions
The manuscript was written by CB, KRB, and ABS and was re-
viewed by all authors. PL, KO, VM, VT, LM, KV, LH, MJJ and MK
made experimental contributions; CB and KB directed research;
and VMYL and JQT provided resources. All authors have given
approval to the final version of the manuscript.
ACKNOWLEDGMENT
13. Wuitschik, G.; Carreira, E. M.; Wagner, B. R.; Fischer, H.;
Parrilla, I.; Schuler, F.; Rogers-Evans, M.; Müller, K.
Oxetanes in drug discovery: structural and synthetic
insights. J. Med. Chem. 2010, 53, 3227-3246.
Financial support for this work has been provided in part by the
NIH/NIA (Grant AG044332-01), the NSF Grant CHE-0840438, (X-
ray facility), and the Marian S. Ware Alzheimer Program.
4
ACS Paragon Plus Environment

Page 5 of 5
ACS Medicinal Chemistry Letters
14. Burkhard, J. A.; Wuitschik, G.; Rogers-Evans, M.; Müller, K.;
21. Soper, J. H.; Sugiyama, S.; Herbst-Robinson, K.; James, M.
1
2
3
4
5
6
7
8
Carreira, E. M. Oxetanes as versatile elements in drug
discovery and synthesis. Angew. Chem. Int. Ed. 2010, 49,
9052-9067.
J.; Wang, X.; Trojanowski, J. Q.; Smith, A. B., III; Lee, V. M.;
Ballatore, C.; Brunden, K. R. Brain-penetrant
tetrahydronaphthalene thromboxane A2-prostanoid (TP)
receptor antagonists as prototype therapeutics for
Alzheimer's disease. ACS Chem. Neurosci. 2012, 3, 928-
940.
15. Croft, R. A.; Mousseau, J. J.; Choi, C.; Bull, J. A. Structurally
Divergent Lithium Catalyzed Friedel–Crafts Reactions on
Oxetan-3-ols: Synthesis of 3,3-Diaryloxetanes and
2,3-Dihydrobenzofurans. Chemistry 2016, 22, 16271-
16276.
16. McLaughlin, M.; Yazaki, R.; Fessard, T. C.; Carreira, E. M.
Oxetanyl peptides: novel peptidomimetic modules for
medicinal chemistry. Org. Lett. 2014, 16, 4070-4073.
17. Möller, G. P.; Müller, S.; Wolfstädter, B. T.; Wolfrum, S.;
Schepmann, D.; Wünsch, B.; Carreira, E. M. Oxetanyl
amino acids for peptidomimetics. Org. Lett. 2017, 19 ,
2510–2513.
22. Huynh, P. N. H.; Walvoord, R. R.; Kozlowski, M. C. Rapid
Quantification of the activating effects of hydrogen-
bonding catalysts with a colorimetric sensor. J. Am. Chem.
Soc. 2012, 134, 15621-15623.
23. Berthelot, M.; Besseau, F.; Laurence, C. The hydrogen-
bond basicity pKHB scale of peroxides and ethers. Eur. J.
Org. Chem. 1998, 1998, 925-931.
24. Tries, S.; Neupert, W.; Laufer, S. The mechanism of action
of the new antiinflammatory compound ML3000:
inhibition of 5-LOX and COX-1/2. Inflamm. Res. 2002, 51,
135-143.
25. Valenti, P.; Rampa, A.; Fabbri, G.; Giusti, P.; Cima, L.
Tetrazole analogs of ibuprofen and flurbiprofen. Arch.
Pharm. (Weinheim, Ger.) 1983, 316, 752-5.
26. Elkady, M.; Niess, R.; Schaible, A. M.; Bauer, J.; Luderer, S.;
Ambrosi, G.; Werz, O.; Laufer, S. A. Modified acidic
nonsteroidal anti-inflammatory drugs as dual inhibitors of
mPGES-1 and 5-LOX. J. Med. Chem. 2012, 55, 8958-62.
27. Boschelli, D. H.; Connor, D. T.; Hoefle, M.; Bornemeier, D.
A.; Dyer, R. D. Conversion of NSAIDS into balanced dual
inhibitors of cyclooxygenase and 5-lipoxygenase. Bioorg.
Med. Chem. Lett. 1992, 2, 69-72.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
18. Beadle, J. D.; Knuhtsen, A.; Hoose, A.; Raubo, P.; Jamieson,
A. G.; Shipman, M. Solid-Phase Synthesis of Oxetane
Modified Peptides. Org. Lett. 2017,
DOI: 10.1021/acs.orglett.7b01466
19. Powell, N. H.; Clarkson, G. J.; Notman, R.; Raubo, P.;
Martin, N. G.; Shipman, M. Synthesis and structure of
oxetane containing tripeptide motifs. Chem. Commun.
2014, 50, 8797-8800.
20. Lassalas, P.; Gay, B.; Lasfargeas, C.; James, M. J.; Tran, V.;
Vijayendran, K. G.; Brunden, K. R.; Kozlowski, M. C.;
Thomas, C. J.; Smith, A. B., III; Huryn, D. M.; Ballatore, C.
Structure property relationships of carboxylic acid
isosteres. J. Med. Chem. 2016, 59, 3183-203.
For Table of Contents Only
5
ACS Paragon Plus Environment