Strategic Incorporation of Polarity in Heme-Displacing Inhibitors of Indoleamine-2,3-dioxygenase-1 (IDO1)

Article abstract of DOI:10.1021/acsmedchemlett.0c00010

Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as a target of significant interest to the field of cancer immunotherapy, as the upregulation of IDO1 in certain cancers has been linked to host immune evasion and poor prognosis for patients. In particular, IDO1 inhibition is of interest as a combination therapy with immune checkpoint inhibition. Through an Automated Ligand Identification System (ALIS) screen, a diamide class of compounds was identified as a promising lead for the inhibition of IDO1. While hit 1 possessed attractive cell-based potency, it suffered from a significant right-shift in a whole blood assay, poor solubility, and poor pharmacokinetic properties. Through a physicochemical property-based approach, including a focus on lowering AlogP₉₈ via the strategic introduction of polar substitution, compound 13 was identified bearing a pyridyl oxetane core. Compound 13 demonstrated improved whole blood potency and solubility, and an improved pharmacokinetic profile resulting in a low predicted human dose.

Full text of DOI:10.1021/acsmedchemlett.0c00010

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Letter
Strategic Incorporation of Polarity in Heme-Displacing
Inhibitors of Indoleamine-2,3-dioxygenase-1 (IDO1)
Catherine White, Meredeth A. McGowan, Hua Zhou, Nunzio Sciammetta, Xavier Fradera, Jongwon
Lim, Elizabeth M Joshi, Christine Andrews, Elliott B. Nickbarg, Phillip Cowley, Sarah Trewick, Martin
Augustin, Konstanze von König, Charles A Lesburg, Karin Otte, Ian Knemeyer, Hyun Woo, Wensheng
Yu, Mangeng Cheng, Peter Spacciapoli, Prasanthi Geda, Xuelei Song, Nadya Smotrov, Patrick Curran,
Mee Ra Heo, Pravien Abeywickrema, J. Richard Miller, David Jonathan Bennett, and Yongxin Han
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.0c00010 • Publication Date (Web): 10 Mar 2020
Downloaded from pubs.acs.org on March 13, 2020
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Strategic Incorporation of Polarity in Heme-Displacing Inhibitors of
Indoleamine-2,3-dioxygenase-1 (IDO1)
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Catherine White*Ω, Meredeth A. McGowan*Ω, Hua ZhouΩ, Nunzio SciammettaΩ, Xavier
Fradera∆, Jongwon LimΩ, Elizabeth M. Joshi℮, Christine Andrews∂, Elliott B. Nickbarg∂, Phillip
Cowley†, Sarah Trewick†, Martin Augustin∑, Konstanze von Köenig∑, Charles A. Lesburg∆, Karin
Otte℮, Ian Knemeyer℮, Hyun Woo℮, Wensheng YuΩ, Mangeng Cheng∏, Peter Spacciapoli∏∞
,
Prasanthi Geda∏, Xuelei Song∏, Nadya Smotrov∏, Patrick Curran∏, Mee Ra Heo∏, Pravien Abey-
wickrema∆†, J. Richard Miller∏, David Jonathan BennettΩ, and Yongxin HanΩ
ΩDepartment of Chemistry, ∆Computational and Structural Chemistry, ∏In Vitro Pharmacology, ℮Pharmacokinet-
ics, Pharmacodynamics & Drug Metabolism, ∂Automated Ligand Identification System
Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States
∑Proteros biostructures GmbH. 82152 Martinsried, Germany
∞Deceased April 15, 2019
KEYWORDS: IDO1, heme displacer, oxetane, AlogP98
ABSTRACT: Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as a target of significant interest to the field of cancer
immunotherapy, as the upregulation of IDO1 in certain cancers has been linked to host immune evasion and poor prognosis
for patients. In particular, IDO1 inhibition is of interest as a combination therapy with immune checkpoint inhibition.
Through an Automated Ligand Identification System (ALIS) screen, a diamide class of compounds was identified as a prom-
ising lead for the inhibition of IDO1. While hit 1 possessed attractive cell-based potency, it suffered from a significant right-
shift in a whole blood assay, poor solubility, and poor pharmacokinetic properties. Through a physicochemical property-
based approach, including a focus on lowering AlogP98 via the strategic introduction of polar substitution, compound 13
was identified bearing a pyridyl oxetane core. Compound 13 demonstrated improved whole blood potency and solubility,
and an improved pharmacokinetic profile resulting in a low predicted human dose.
Indoleamine-2,3-dioxygenase-1 (IDO1) is a heme-con-
taining enzyme which catalyzes the oxidation of essential
amino acid tryptophan (Trp) as the first and rate-limiting
step of the kynurenine pathway. Both depletion of Trp and
the production of kynurenine and other pathway metabo-
lites contribute to local immunosuppression, manipulating
multiple components of the innate and adaptive immune
system including CD8+ T cells, effector T (Teff) cells, and
natural killer (NK) cells.1-4 Many human tumors have been
shown to exploit this pathway by upregulating the
expression of IDO1,5-7 and an increased level of IDO1 ex-
pression in tumor cells is correlated with poor prognosis in
several tumor types.8, 9 Given its role in contributing to im-
mune escape, IDO1 has emerged as an important therapeu-
tic target in cancer immunotherapy.10, 11 Initial proof of con-
cept for IDO1 inhibition in the clinic was established with
13
epacadostat12,
in combination with anti-PD-1 (pro-
grammed cell death protein 1) antibodies.14 The recent fail-
ure of this combination to show improved efficacy over
anti-PD-1 monotherapy in a phase 3 study (ECHO-
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301/KEYNOTE-252) has prompted speculation that epoca-
dostat may have failed to achieve sufficient target engage-
ment in the tumor microenvironment.15 Thus, the investi-
gation of IDO1 inhibition continues in the clinic,16 and it
remains highly desirable to discover new highly potent and
selective IDO1 inhibitors which allow for achievement of
higher levels of target engagement.
Ser267 and Arg343. The aryl amide extends below the
plane of the absent heme to occupy a largely hydrophobic
pocket (which we termed the “C” pocket). The n-propyl
amide substituent extends into and partially filled a hydro-
phobic pocket above the absent heme (termed the “A”
pocket),17 which in the case of compound 2 is occupied by
an aryl substituent.
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Over the past several years, there have been multiple re-
ports describing alternative binding modes and mecha-
nisms of action for IDO1-selective inhibitory small mole-
cules. Epacadostat inhibits IDO1 via a competitive binding
mechanism, occupying the Trp binding site and coordinat-
ing to the heme-bound iron, while an uncompetitive inhib-
itor such as mitomycin C occupies an allosteric site located
on the opposite side of the heme in the protein.17 Addi-
tionally, it has recently been demonstrated that the heme
cofactor is labile and can be displaced entirely, allowing for
inhibitors to bind to the apoenzyme and thus prevent
heme from re-binding.18 In fact, it has been shown that a
majority of IDO1 present in the cell is in its apo form. This
class of inhibitors are therefore particularly effective in a
cellular setting, but require extended incubation times and
elevated temperatures to effect inhibition in a functional
enzymatic assay where the heme is pre-incorporated.
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As part of our efforts towards identifying a small mole-
cule inhibitor of IDO1, we performed an affinity-based pri-
mary screen of 260,000 compounds against IDO1 using Au-
tomated Ligand Identification System (ALIS) technology.
This screening method relies on identification of small
molecules which bind to a target of interest via a mass-
spectrometry-based detection using pooled libraries of
compounds with known and distinct masses.19-21,22 Signifi-
cantly, the protein employed for this screen was found to
have achieved between 80% and 90% heme incorporation
during its biosynthesis, and thus both apo and heme-
bound forms of the protein were present (see Supporting
Information for protein preparation protocol). From this
screening campaign, diamide 1 was identified as a promis-
ing hit, displaying potent activity in a HeLa cell-based as-
say measuring production of the product of IDO1-
mediated tryptophan oxidation, N-formylkynurenine
(Hela IC50 = 9 nM, see Supporting Information for assay
details). Interestingly, 1 was inactive in a biochemical IDO1
inhibition assay, prompting speculation that 1 acts as a
As an initial lead, compound 1 displayed potent suppres-
sion of N-formylkynurenine production in HeLa cells, cou-
pled with promising unbound potency (22 nM) as assessed
in a whole blood assay measuring kynurenine production
and corrected for human plasma protein binding27 (Table
1). However, compound 1 suffered from high turnover in
in vitro microsome and hepatocyte systems,28 and a short
mean residence time (MRT) when dosed in vivo. In light of
this data, the predicted once-daily (QD, or quaque die) hu-
man dose for compound 1, as estimated by allometric scal-
ing based on rat pharmacokinetic parameters,29 was in ex-
cess of 10g QD (See Supporting Information for details).
heme-displacing IDO1 inhibitor as described above.23
A
high-resolution co-crystal structure was obtained with apo
IDO1 and compound 1 (Figure 1; PDB [protein database]
entry 6V52), which confirmed that 1 binds in such a man-
ner that it occupies the binding site of the absent heme co-
factor. This binding mode is further illustrated by an over-
lay24 of the crystal structure of 1 with a recently disclosed
heme-displacing inhibitor (compound 2, Figure 2)18,25 and
heme (PDB entry 6e40).26 The structure also reveals that 1
is anchored to the protein via a network of hydrogen
bonds, extending from the propyl-substituted amide di-
rectly to Ser167 and (via water) His346, as well as two wa-
ter-mediated hydrogen bonds from the aryl amide to
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are highly protein-bound in human plasma, it was useful
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to compare unbound potency values as measured in the
human whole blood assay to decouple the plasma protein
binding and target interaction components. Gratifyingly,
the introduction of a more polar pyran substituent, for ex-
ample, resulted in greater in vitro stability (compound 4).
Unfortunately, most polar substitution was not tolerated
in either of the largely hydrophobic pockets in terms of po-
tency, and in this sense only minor changes were tolerated
(compound 6). A notable exception was compound 5,
which featured a 2-substituted pyridine. However, while
this compound possessed favorable solubility, it also car-
ried a significant hERG (human Ether-a-go-go-Related
Gene) liability (420 nM in a hERG binding assay) and was
not pursued further.
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Metabolic identification (MetID) assessments were con-
ducted on compound 1 to identify primary metabolic lia-
bilities, and the results indicated that initial oxidative me-
tabolism occurred on the n-propyl group in rat and human
microsomes, and additionally that the aryl amide bond was
readily cleaved in human hepatocyctes (Figure 3). To ad-
dress the propyl group oxidation, and guided by the crystal
structure which suggested an opportunity to further opti-
mize van der Waals interactions in the A-pocket, com-
pound 3 was synthesized which incorporated a fluoro-
phenyl amide. A significant increase in both HeLa and
whole blood potency was observed with compound 3 as
compared to 1, however the human hepatocyte turnover
remained high. In addition, a significant drop in solubility
was observed, which was hypothesized to lead to compli-
cations with respect to formulation and dosing.
Having concluded from these initial explorations that
substituents projecting into the A- and C-pockets must re-
main hydrophobic, attention was turned towards explora-
tion of polar functionality in the central core of the hit
structure. In the context of the fluorophenyl group at the
R1 position, a pyridine was tolerated in place of the central
phenyl ring (compound 9), resulting in a compound with
comparable HeLa potency and 6-fold shifted unbound
hWB (human whole blood) potency. Additionally, 9 dis-
played improved kinetic solubility while maintaining
hepatocyte stability with respect to 3. Interestingly, pyrim-
idine substitution (10) did not improve solubility, despite
its lowered AlogP98 value, and furthermore was not toler-
ated in terms of potency.
As outlined above, it is of significant importance that the
next generation of IDO1 inhibitors are capable of achieving
high levels of target engagement in clinical trials. As such,
our goal was to identify a compound predicted to require a
low dose to achieve excellent levels of target engagement
in humans, which we defined as the ability to achieve
greater than 75% inhibition (or IC75 as measured in the
whole blood assay) over a 24h period. While highly potent,
In addition to the phenyl portion of the core, the cyclo-
butane offered an opportunity for the introduction of polar
substituents. We hypothesized that an oxetane, as a polar,
metabolically robust cyclobutane alternative,35-38 would
significantly lower the compound lipophilicity with mini-
mal effect on compound binding. Indeed, introduction of
an oxetane dramatically lowered the AlogP98 to 3.8 (com-
pound 11), and a corresponding improvement in hepato-
cyte stability was observed as compared to 3. Moreover, 11
did not suffer from any potency loss as a result of the in-
troduction of the oxetane. To further investigate polar sub-
stitution in the cyclobutane region, compound 12 was syn-
thesized featuring a hydroxycyclobutane. While com-
pound 12 also displayed improved in vitro stability as com-
pared to 3, the hydroxy substitution was not tolerated in
the binding pocket and both HeLa and hWB potencies
were significantly shifted. Finally, we sought to combine
the successful polar core substitutions into a single analog
featuring a 2-pyridyl oxetane (compound 13). Compound
13 displayed an excellent unbound hWB potency of 0.6 nM,
and dramatically improved FaSSIF (fasted simulated small
intestinal fluid) solubility (170 µM) (see Supporting Infor-
mation for experimental procedure to determine FaSSIF
solubility). Moreover, compound 13 possessed excellent
stability in both human and rat hepatocytes, as it was com-
pletely stable over the course of the experiment.
30
compound 3 is also highly lipophilic (AlogP98 = 5.3), re-
siding outside of traditional drug-like space.31, 32 This high
lipophilicity is likely contributing to poor solubility and in
vitro hepatocyte stability. It has been demonstrated in the
medicinal chemistry literature that modulation of physico-
chemical properties such as AlogP98 can have a dramatic
34
effect on pharmacokinetic parameters.33,
Therefore,
moving forward, one of our strategies for the optimization
of this series of IDO1 inhibitors was to seek opportunities
to introduce polarity to aspirationally improve both meta-
bolic stability as well as compound solubility.
Given the modular nature of the hit scaffold, with amide
bonds amenable to structure-activity relationship (SAR)
exploration via amide library synthesis, initial efforts fo-
cused on the rapid exploration of alternative substitution
in the A- and C- pockets in the background of compound 1
and with a focus on the addition of polar functionality. Se-
lected examples of this exploration are depicted in Table 1
(compounds 4-8). As many of the compounds in this series
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Over the 108 protein targets evaluated, there were no tar-
gets for which the IC50 of compound 13 was <10 µM (see
Supporting Information). It is worthwhile to note that
compound 9 was also evaluated in the same panel, and was
found to hit 4 targets below the 10 µM threshold. This im-
proved off-target profile may be at least partially attributed
to a lower AlogP98, a phenomenon that has been noted in
numerous discovery efforts reported in the literature.40-43
Thus, pyridyl oxetane 13 represented an attractive com-
pound for further development as a low-dose QD inhibitor
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of
IDO1.
Selected compounds depicted in Table 1 were further pro-
filed in vivo and evaluated for a predicted human dose, as
depicted in Table 2. Initial hit compound 1, which was
demonstrated above to be readily oxidized at the propyl
group, was also rapidly cleared in a rat cassette and dis-
played plasma clearance greater than rat hepatic blood
flow. Replacing the propyl group with the fluorophenyl
group (compound 3) resulted in a dramatic improvement
in MRT and a low allometry-predicted dose. However, as
mentioned above, the compound was unattractive due to
poor solubility. The introduction of a pyridine (compound
9) maintained the favorable rat MRT as compared to com-
pound 3, however the predicted dose was shifted due to a
six-fold decrease in intrinsic whole blood potency. The in-
troduction of the oxetane into the core (11) also served to
maintain a favorable rat MRT and similar intrinsic whole
blood potency, however 11 was significantly less stable in
human hepatocytes as compared to rat, and for this reason
there was uncertainty around the allometry-predicted dose
(see Supporting Information). Finally, pyridyl oxetane
compound 13 displayed a favorable rat MRT of 3.2h, and
moreover was more stable both as reflected by the in vivo
Clint39 (intrinsic clearance) and in vitro hepatocyte stability
across species as mentioned above. This stability, favora-
ble rat PK (pharmacokinetics), and improved solubility,
combined with excellent potency, resulted in a human QD
dose prediction of 26 mg (Table 2).
Despite its utility and metabolic stability as demon-
strated above, the pyridyl oxetane substitution pattern lev-
eraged in lead compound 13 was not previously reported in
the literature. To rapidly access this core, it was found that
commercially available oxetane-3-carbonitrile (15) could
be directly deprotonated through the use of potassium
bis(trimethylsilyl)amide (KHMDS) at reduced tempera-
tures, and that this nucleophile could be readily added to
5-bromo-2-fluoropyridine (14) to provide 3-(5-bro-
mopyridin-2-yl)oxetane-3-carbonitrile (16) in reasonable
yields (Scheme 1).44 The nitrile could then be hydrolyzed
to the carboxylic acid (17), after which, for the purposes of
this series, could engage in an amide coupling to provide
19. Compound 19 was then subjected to copper-catalyzed
C-N coupling conditions to provide lead compound 13.
In conclusion, an affinity-based screening method
(ALIS) led to the rapid identification of a diamide-contain-
ing IDO1 heme-displacing inhibitor with promising cell-
To further assess the suitability of compound 13 as a lead
compound, 13 was profiled in a panel of off-target assays.
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bis(trimethylsilyl)amide; C-N couplings, carbon-nitrogen
based potency, but which suffered from high clearance and
a significant whole blood shift. Through a crystal structure-
inspired optimization of A-pocket substitution, it was dis-
covered that a phenyl group significantly enhanced po-
tency. A subsequent physicochemical property-led inves-
tigation of SAR (structure–activity relationship) led to the
discovery that a strategic incorporation of polarity into the
core of the structure was tolerated in terms of potency and
greatly enhanced the pharmacokinetic profile of the result-
ing compounds. These investigations resulted in a lead
compound with an excellent predicted human dose and a
favorable off-target profile for further development.
1
2
3
4
5
6
7
8
couplings; NaOH, sodium hydroxide; HATU, 1-[Bis(dimethyl-
amino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide
hexafluorophosphate; DIEA, N,N-Diisopropylethylamine;
DMF, dimethylformamide; Cs2CO3, cesium carbonate; Cu(I)I,
Copper(I) iodide; PK, pharmacokinetics; SAR, structure–activ-
ity relationship.
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ASSOCIATED CONTENT
Supporting Information
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Prendergast, G. C.;
Malachowski, W. P.;
The Supporting Information is available free of charge on the
ACS Publications website.
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The crystal structure of human IDO1 in complex with com-
pound 1 has been deposited at the PDB (http://www.rcsb.org)
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expanding range of targets for kynurenine metabolites of
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3252.
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Rauschenbach, K. J.; Trump, S.; Winter, M.; Ott, M.; Ochs,
K.; Lutz, C.; Liu, X. D.; Anastasov, N.; Lehmann, I.; Hofer,
T.; von Deimling, A.; Wick, W.; Platten, M., Constitutive IDO
expression in human cancer is sustained by an autocrine
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Present Addresses
†Phillip Cowley (PMC Discovery Limited, Edinburgh, United
Kingdom), †Sarah Trewick (Edinburgh Innovations, Edin-
burgh, United Kingdom), †Pravien Abeywickrema (The
Janssen Pharmaceutical Companies of Johnson and Johnson,
Pennsylvania), †Prasanthi Geda (AbbVie, Illinois)
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Author Contributions
The manuscript was written through contributions of all au-
thors. All authors have given approval to the final version of
the manuscript.
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Kong, L. D.; Zhu, Z. M., The Clinicopathological and
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Analysis. Cell Physiol Biochem 2018, 49 (1), 134-143.
ACKNOWLEDGMENT
Chad Chamberlin, Omar Mabrouk, Patrick Curran, Matt Rich-
ards, and Peter Saradjian for their contributions to the ALIS
screen. Lisa Nogle, David Smith, and Mark Pietrafitta for their
contributions as members of the Separation Sciences Team.
Adam Beard for his contributions to high quality purity deter-
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9421-9437.
ABBREVIATIONS
11.
Platten, M.; Doeberitz, N. V.; Oezen, I.; Wick, W.;
ALIS, Automated Ligand Identification System; IDO1, In-
doleamine-2,3-dioxygenase-1; hWBu, human whole blood, un-
bound potency; FaSSIF, fasted simulated small intestinal fluid;
Clint, intrinsic clearance; Vdu Volume of distribution un-
bound; MRT, Mean residence time; PD-1, Programmed cell
death protein 1; PDB, protein database; QD, quaque die;
MetID, Metabolic identification; hERG, human Ether-a-go-
Ochs, K., Cancer immunotherapy by targeting IDO1/TDO and
their downstream effectors. Front Immunol 2015, 5.
12.
Yue, E. W.; Douty, B.; Wayland, B.; Bower, M.; Liu,
X. D.; Leffet, L.; Wang, Q.; Bowman, K. J.; Hansbury, M. J.;
Liu, C. N.; Wei, M.; Li, Y. L.; Wynn, R.; Burn, T. C.; Koblish,
H. K.; Fridman, J. S.; Metcalf, B.; Scherle, P. A.; Combs, A. P.,
Discovery of Potent Competitive Inhibitors of Indoleamine
go-Related
Gene;
KHMDS,
Potassium
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2,3-Dioxygenase with in Vivo Pharmacodynamic Activity and
Efficacy in a Mouse Melanoma Model. J Med Chem 2009, 52
(23), 7364-7367.
Discovery. In M. L. Gross, G. Chen, & B. N. Pramanik (Eds.),
Protein and Peptide Mass Spectrometry in Drug Discovery
(pp. 255-286). Hoboken, NJ: John Wiley & Sons, Inc.
1
2
3
4
5
6
7
8
13.
Koblish, H. K.; Hansbury, M. J.; Bowman, K. J.;
23.
See Supporting Information for IDO1 biochemical
Yang, G. J.; Neilan, C. L.; Haley, P. J.; Burn, T. C.; Waeltz, P.;
Sparks, R. B.; Yue, E. W.; Combs, A. P.; Scherle, P. A.; Vaddi,
K.; Fridman, J. S., Hydroxyamidine Inhibitors of Indoleamine-
2,3-dioxygenase Potently Suppress Systemic Tryptophan
Catabolism and the Growth of IDO-Expressing Tumors. Mol
Cancer Ther 2010, 9 (2), 489-498.
and HeLa assay protocols.
24.
Overlays were rendered in The PyMOL Molecular
Graphics System, Version 2.1.1 Schrödinger, LLC
25.
Beck, H.P et al(2016) Patent Cooperation Treaty Int
Appl WO 2016073770.
26.
Luo, S.; Xu, K.; Xiang, S.; Chen, J.; Chen, C.; Guo,
9
14.
Beatty, G. L.; O'Dwyer, P. J.; Clark, J.; Shi, J. G.;
C.; Tong, Y.; Tong, L., High-resolution structures of inhibitor
complexes of human indoleamine 2,3-dioxygenase 1 in a new
crystal form. Acta Crystallogr F Struct Biol Commun 2018, 74
(Pt 11), 717-724.
10
11
12
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23
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27
28
29
30
31
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34
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36
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44
45
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49
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58
59
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Bowman, K. J.; Scherle, P. A.; Newton, R. C.; Schaub, R.;
Maleski, J.; Leopold, L.; Gajewski, T. F., First-in-Human Phase
I Study of the Oral Inhibitor of Indoleamine 2,3-Dioxygenase-
1 Epacadostat (INCB024360) in Patients with Advanced Solid
Malignancies. Clin Cancer Res 2017, 23 (13), 3269-3276.
27.
The value for unbound human whole blood IC50 was
obatained using the following equation: hWBu = (measured
IDO1 hWB IC50) * (Human fu plasma)
15.
Muller, A. J.; Manfredi, M. G.; Zakharia, Y.;
Prendergast, G. C. J. S. i. I., Inhibiting IDO pathways to treat
cancer: lessons from the ECHO-301 trial and beyond. Semin
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28.
Please see the Supporting Information for
experimental details regarding in vitro compound stability in
hepatocyte and microsome systems.
16.
Komiya, T.; Huang, C. H., Updates in the Clinical
29.
Hosea, N. A.; Collard, W. T.; Cole, S.; Maurer, T. S.;
Development of Epacadostat and Other Indoleamine 2,3-
Dioxygenase 1 Inhibitors (IDO1) for Human Cancers. Front
Oncol 2018, 8.
Fang, R. X.; Jones, H.; Kakar, S. M.; Nakai, Y.; Smith, B. J.;
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17.
Lewis-Ballester, A.; Pham, K. N.; Batabyal, D.;
Karkashon, S.; Bonanno, J. B.; Poulos, T. L.; Yeh, S. R.,
Structural insights into substrate and inhibitor binding sites
in human indoleamine 2,3-dioxygenase 1. Nat Commun 2017,
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Ghose, A. K.; Viswanadhan, V. N.; Wendoloski, J. J.,
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Nelp, M. T.; Kates, P. A.; Hunt, J. T.; Newitt, J. A.;
Balog, A.; Maley, D.; Zhu, X.; Abell, L.; Allentoff, A.;
Borzilleri, R.; Lewis, H. A.; Lin, Z. Y.; Seitz, S. P.; Yan, C. H.;
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Lipinski, C. A., Drug-like properties and the causes
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Lipinski, C. A.; Lombardo, F.; Dominy, B. W.;
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Kutilek, V. D.; Andrews, C. L.; Richards, M. P.; Xu,
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Z. W.; Sun, T. X.; Chen, Y. P.; Hashke, A.; Smotrov, N.;
Fernandez, R.; Nickbarg, E. B.; Chamberlin, C.; Sauvagnat,
B.; Curran, P. J.; Boinay, R.; Saradjian, P.; Allen, S. J.; Byrne,
N.; Elsen, N. L.; Ford, R. E.; Hall, D. L.; Kornienko, M.;
Rickert, K. W.; Sharma, S.; Shipman, J. M.; Lumb, K. J.;
Coleman, K.; Dandliker, P. J.; Kariv, I.; Beutel, B., Integration
of Affinity Selection-Mass Spectrometry and Functional Cell-
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Lazerwith, S. E.; Bahador, G.; Canales, E.; Cheng, G.
F.; Chong, L.; Clarke, M. O.; Doerffler, E.; Eisenberg, E. J.;
Hayes, J.; Lu, B.; Liu, Q.; Matles, M.; Mertzman, M.;
Mitchell, M. L.; Morganelli, P.; Murray, B. P.; Robinson, M.;
Strickley, R. G.; Tessler, M.; Tirunagari, N.; Wang, J. H.;
Wang, Y. J.; Zhang, J. R.; Zheng, X. B.; Zhong, W. D.; Watkins,
W. J., Optimization of Pharmacokinetics through
Manipulation of Physicochemical Properties in a Series of
HCV Inhibitors. Acs Med Chem Lett 2011, 2 (10), 715-719.
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Annis, D. A.; Athanasopoulos, J.; Curran, P. J.;
Felsch, J. S.; Kalghatgi, K.; Lee, W. H.; Nash, H. M.; Orminati,
J. P. A.; Rosner, K. E.; Shipps, G. W.; Thaddupathy, G. R. A.;
Tyler, A. N.; Vilenchik, L.; Wagner, C. R.; Wintner, E. A., An
affinity selection-mass spectrometry method for the
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Meanwell, N. A., Improving Drug Design: An Update
on Recent Applications of Efficiency Metrics, Strategies for
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35.
Wuitschik, G.; Rogers-Evans, M.; Muller, K.;
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Annis, D. A.; Nickbarg, E.; Yang, X.; Ziebell, M. R.;
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Burkhard, J. A.; Wuitschik, G.; Rogers-Evans, M.;
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Andrews, C. L., Ziebell, M. R., Nickbarg, E., & Yang,
X. (2012). Mass Spectrometry-Based Screening and
Characterization of Protein–Ligand Complexes in Drug
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Stepan, A. F.; Karki, K.; McDonald, W. S.; Dorff, P.
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Peters, J. U.; Schnider, P.; Mattei, P.; Kansy, M.,
1
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Efremov, I. V.; O'Donnell, C. J.; Nolan, C. E.; Becker, S. L.;
Pustilnik, L. R.; Sneed, B.; Sun, H.; Lu, Y. S.; Robshaw, A. E.;
Riddell, D.; O'Sullivan, T. J.; Sibley, E.; Capetta, S.; Atchison,
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Decrescenzo, G. A.; Devraj, R. V.; Ellsworth, E.; Fobian, Y.
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Design
of
Oxetane-Containing
38.
Toselli, F.; Fredenwall, M.; Svensson, P.; Li, X. Q.;
9
Johansson, A.; Weidolf, L.; Hayes, M. A., Hip To Be Square:
Oxetanes as Design Elements To Alter Metabolic Pathways. J
Med Chem 2019, 62 (16), 7383-7399.
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39.
The value for rat in vivo Clint was obtained using the
following equation: Rat in vivo Clint = [Qh*Clp] / [fu,p*(Qh-
(Clp/B:P))]
44.
For
a
similar transformation involving
a
cyclobuntane nitrile, see: Lemieux, R. M. et al(2009) Patent
Cooperation Treaty Int Appl WO 2009070485.
40.
Koslov-Davino, E.; Wang, X.; Schroeter, T., Target
promiscuity and physicochemical properties contribute to
pharmacologically induced ER-stress. Toxicol In Vitro 2013, 27
(1), 204-10.
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