Addition of Fluorine and a Late-Stage Functionalization (LSF) of the Oral SERD AZD9833

Article abstract of DOI:10.1021/acsmedchemlett.0c00505

Herein we describe our efforts using a late stage functionalization together with more traditional synthetic approaches to generate fluorinated analogues of the clinical candidate AZD9833. The effects of the addition of fluorine on the lipophilicity, permeability, and metabolism are discussed. Many of these changes were tolerated in terms of pharmacology and resulted in high quality molecules which reached advanced stages of profiling in the testing cascade.

Full text of DOI:10.1021/acsmedchemlett.0c00505

pubs.acs.org/acsmedchemlett
Letter
Addition of Fluorine and a Late-Stage Functionalization (LSF) of the
Oral SERD AZD9833
James S. Scott,* Thomas A. Moss,* Bernard Barlaam, Paul R. J. Davey, Gary Fairley, Eric T. Gangl,
Ryan D. R. Greenwood, Holia Hatoum-Mokdad, Andrew S. Lister, David Longmire, Radoslaw Polanski,
Stephen Stokes, Michael J. Tucker, Jeffrey G. Varnes, and Bin Yang
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ABSTRACT: Herein we describe our efforts using a late stage functionalization together
with more traditional synthetic approaches to generate fluorinated analogues of the clinical
candidate AZD9833. The effects of the addition of fluorine on the lipophilicity,
permeability, and metabolism are discussed. Many of these changes were tolerated in
terms of pharmacology and resulted in high quality molecules which reached advanced
stages of profiling in the testing cascade.
KEYWORDS: Estrogen receptor degrader, fluorine, LSF, medicinal chemistry
eplacement of hydrogen by a fluorine is a commonly
further enhance benefit to patients.16,17 We recently disclosed
our efforts leading to the discovery of the oral SERD AZD9833
(1) (Figure 1), which is currently being evaluated in phase II
1
Remployed strategy in medicinal chemistry.
The high
electronegativity of fluorine results in strong, polarized C−F
bonds which can be resistant to metabolism, undergo
interactions with proteins, and allow modulation of phys-
icochemical properties.2,3 The utility of this atom is reflected in
the high proportion of launched drugs4,5 and molecules
currently in development6 that contain fluorine within their
molecular structures. The increased application of fluorine in
drug discovery programs has advanced in tandem with
improved synthetic methodologies for C−F bond forma-
tion.7−9
Late stage functionalization (LSF) is an emerging paradigm,
driven by advances in C−H activation chemistry, for
generating close analogues of lead molecules.10 It has the
potential to rapidly expand structure activity relationships
(SAR) and access substitution patterns that are challenging to
achieve using traditional synthetic approaches. Given the
importance of fluorine, a number of LSF approaches targeting
its introduction have recently been described.11,12
Figure 1. Fulvestrant and AZD9833 (1).
clinical trials.18 Notably, both fulvestrant and 1 already contain
multiple fluorine atoms (5 and 4, respectively). Herein, we
report some of our efforts during the discovery program to
generate fluorinated analogues of 1 and showcase some of the
synthetic strategies employed to achieve this.
Degradation and antagonism of the estrogen receptor α
(ERα) is a clinically validated approach for the treatment of
breast cancer.13 Fulvestrant, a selective estrogen receptor
degrader (SERD) which has the ability to both completely
antagonize ERα signaling and cause degradation of the protein,
was approved for second-line treatment of hormone receptor
positive metastatic breast cancer nearly two decades ago.14
Fulvestrant is administered clinically via monthly intramuscular
injection, with a maximum administrable dose of 500 mg and is
currently the only clinically approved SERD.15 Recent efforts
have been made to discover orally bioavailable SERDs to
Our initial efforts focused on introducing fluorine to the
pyridyl D-ring. We anticipated that late-stage electrophilic
fluorination of the relatively electron-poor pyridine would be
Received: September 17, 2020
Accepted: October 23, 2020
https://dx.doi.org/10.1021/acsmedchemlett.0c00505
© XXXX American Chemical Society
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challenging in the presence of the indazole moiety. In addition,
oxidative approaches such as Hartwig’s ortho-fluorination of
pyridines19 can be sensitive to additional functionality.
Drawing on our prior experience from the discovery program
that led to 1,18 we expected that the desired tricyclic indazoles
should be accessible from a Pictet−Spengler cyclization of a
pyridyl aldehyde with the indazole 16 (Scheme 1). Using this
Table 1. Pyridyl D-Ring Substitution
a
Scheme 1. Synthesis of Pyridyl D-Ring Analogues 2 and 3
c
ER bind
a
ER DR
b
LogD
Hu % Rat heps Hu mics
d
e
f
Cpd
pIC50
pIC50
(LLE)
Free
Clint
Clint
1
2
3
8.6
8.8
8.7
9.8 (99%)
9.7 (98%)
9.6 (98%)
2.9 (6.9)
3.0 (6.7)
3.0 (6.6)
23
16
16
23
36
24
12
20
19
a
b
ER binding based on n ≥ 2 with SEM within 0.3 units. ER
c
degradation based on n ≥ 2 with SEM within 0.3 units. logD7.4
determined by shake flask method with LLE (ER DR pIC50-logD7.4).
d
Plasma protein binding determined from DMSO stock solution by
equilibrium dialysis in 10% human plasma supplied by Quintiles.
e
Rate of metabolism (μL/min/106 cells) determined from DMSO
stock solution in isolated rat hepatocytes diluted to 1 × 106 cells/mL.
a
f
Reagents and conditions: (a) (MeO)3CH, In(OTf)3, 71%; (b) AgF2,
Rate of metabolism (μL/min/mg) determined from DMSO stock
MeCN, 58%; (c) HCl, THF, 96%; (d) 5-bromo-3-fluoropicolinalde-
hyde or 15, toluene/TFA (9:1), 90 °C, 62−64%; (e) 1-(3-
fluoropropyl)azetidin-3-amine, BrettPhos third generation precatalyst,
NaOtBu, 1,4-dioxane, 50 °C, 71% for 2, 49% for 3.
solution in human microsomes.
a
Scheme 2. Synthesis of Phenyl B-Ring Analogue 4
approach, the required fluorination pattern could be
introduced on a much simpler pyridine substrate. 5-Bromo-
3-fluoropicolinaldehyde was readily accessible from commer-
cial suppliers; however, there was very limited availability for
the 6-fluoro analogue 15. We accessed this by initial protection
of 5-bromopicolinaldehyde as the dimethyl acetal. Hartwig
fluorination19 using AgF2 in MeCN smoothly introduced the
desired fluorine onto the remaining ortho position of the
pyridine, after which acidic hydrolysis of the acetal furnished
the desired fluoro-aldehyde in good yield. Pleasingly, both
aldehydes readily underwent Pictet−Spengler cyclization to
afford the tricyclic indazoles 17 and 18. Finally, Buchwald
amination catalyzed by BrettPhos third generation palladium
precatalyst20 installed the desired amino-azetidine to afford
fluoro-pyridines 2 and 3.
Both 2-F (2) and 5-F (3) substitutions produced
compounds with very similar potencies (Table 1) and only
minimal increase in lipophilicity (ΔlogD + 0.1). The
degradation was confirmed by Western blot in both MCF-7
and CAMA-1 cell lines and was similar to that observed with
1.21 No significant changes were observed in either free drug
levels or rat hepatocyte clearance; however, changes were
observed in terms of permeability. Compound 1 showed good
permeation (Papp = 13 × 10−6 cm/s) with modest levels of
efflux (ER = 4) in a Caco-2 assay.22 F-analogue 2, with the F
a
Reagents and conditions: (a) n-BuLi, tert-butyl (R)-4-methyl-1,2,3-
oxathiazolidine-3-carboxylate-2,2-dioxide, THF, −78 °C, 64%; (b)
HCl, DCM, 99%; (c) ethyl 2,2,2-trifluoroacetate, Et3N, MeOH, 98%;
(d) BH3·THF, THF, 71%; (e) 5-bromopicolinaldehyde, toluene/TFA
(20:1), 90 °C, 80%; (f) 1-(3-fluoropropyl)azetidin-3-amine, Brett-
Phos third generation precatalyst, NaOtBu, 1,4-dioxane, 50 °C, 54%.
the cyclic sulfamidate.23 Deprotection of the N-Boc group and
alkylation of the amine salt in a 2-step procedure furnished the
alkylated indazole 20 in good overall yield. The desired
tricyclic indazole 4 was subsequently accessed in the same
manner as previous compounds; Pictet−Spengler cyclization
with 5-bromopicolinaldehyde was followed by Buchwald
amination to install the amino-azetidine group.
Although 4-bromo-6-fluoroindazole was available from
commercial suppliers, we were able to harness a late-stage
functionalization approach to access this and other substituents
on the 6-position from a common substrate (Scheme 3).
Starting from the THP-protected tricyclic indazole 21 (see SI
for details), iridium catalyzed borylation24 successfully installed
the pinacol boronate as a single regioisomer, which was
presumably directed by the neighboring pyridine.25,26 The N2
THP isomer was chosen to avoid a potential competitive
directing effect from the oxygen to the 7-position of the
indazole that might be anticipated from the alternative N1
protected isomer.27 From this common intermediate, azidation
of the boronate28 followed by reduction afforded the aniline
23. The Balz−Schiemann reaction converted this aniline into
the fluorine,29 along with concomitant cleavage of the THP
protecting group. Finally the azetidine was installed by
Buchwald amination to produce the 6-fluorinated indazole 5.
proximal to the NH, showed an increased permeability (Papp
=
24 × 10−6 cm/s) and no efflux (ER = 0.8), potentially due to
shielding of the donor by the neighboring fluorine. By contrast,
isomeric 3, bearing the F distal to the NH, did not show
improvements in either permeability (Papp = 14 × 10−6 cm/s)
or efflux (ER = 7).
We next turned our attention to the B-ring of the tricyclic
scaffold (Scheme 2). As a start-point 4-bromo-7-fluoroindazole
was available from commercial suppliers. Again drawing on our
previous experience, the required alkylated indazole could be
accessed by reacting the preformed organolithium species with
B
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a
While none of these compounds offered improvements over
the unsubstituted core, LSF allowed rapid exploration of SAR
at the 6-position and convinced us not to invest further
chemistry exploring this region.
Scheme 3. Synthesis of Phenyl B-Ring Analogues 5−7
Fluorination of the A-ring of the indazole was explored in
conjunction with fluorination of the pyridyl ring explored in
Table 1 (Scheme 4). Electrophilic fluorination of the tricyclic
a
Scheme 4. Synthesis of Indazole A-Ring Analogues 8 and 9
a
Reagents and conditions: (a) [Bpin]2, [Ir(OMe)(cod)]2, THF, 66 °C,
64%; (b) NaN3, CuSO4, MeOH, RT, then NaBH4, 66%; (c) NaNO2,
HBF4, THF/H2O, 150 °C, 8%; (d) 1-(3-fluoropropyl)azetidin-3-
amine, BrettPhos third generation precatalyst, NaOtBu, 1,4-dioxane,
70 °C, 25%; (e) Cu(OTf)2, CsF, MeOH, RT, 56%; (f) NaBO3, THF/
H2O; (g) 4 N HCl in dioxane, MeOH, RT, 82% from 24, 49% over 2
steps from 25 including step f; (h) 1-(3-fluoropropyl)azetidin-3-
amine, BrettPhos third generation precatalyst, NaOtBu, 1,4-dioxane,
65−70 °C, 29% for 6, 4% for 7.
a
Reagents and conditions: (a) Selectfluor, DMA, 26%; (b) n-BuLi, tert-
butyl (R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate-2,2-dioxide,
THF, −78 °C, 90%; (c) 4 N HCl in dioxane, RT, 94%; (d) 2,2,2-
trifluoroethyl trifluoromethanesulfonate, DIPEA, 1,4-dioxane, 94%;
(e) 5-bromo-6-fluoropicolinaldehyde or 5-bromo-3-fluoropicolinalde-
hyde, toluene/TFA (9:1), 90 °C, 69−82%; (f) 1-(3-fluoropropyl)-
azetidin-3-amine, BrettPhos third generation precatalyst, NaOtBu, 1,4-
dioxane, 90 °C, 58% for 8, 64% for 9.
indazole proved to be unsuccessful due to unwanted oxidation
of the relatively labile C−H bond in the piperidine ring,
leading to formation of an iminium ion. To mitigate against
this inherent reactivity toward oxidants, we decided to install
the 3-fluoro at an earlier stage. Treatment of 4-bromoindazole
with Selectfluor in DMA afforded 4-bromo-3-fluoroindazole 26
in modest yield.32 From here, a similar procedure to Scheme 2
was employed; formation of the organolithium and reaction
with the cyclic sulfamidate gave the free amine after removal of
the N-Boc group. Subsequent alkylation produced 27 which
underwent Pictet−Spengler cyclization smoothly with both
fluorinated aldehydes. Finally, Buchwald amination installed
the amino-azetidine to afford 8 and 9.
The pinacol boronate 22 also allowed access to the methoxy
analogue 24, by treatment with Cu(OTf)2 and CsF in
MeOH,30 and the phenol 25, by reaction with NaBO3 in
THF/H2O.31 In both cases deprotection of the THP group
followed by Buchwald amination gave the 6-methoxy and 6-
hydroxy substituted indazoles 6 and 7.
The 7-F (4) substitution was tolerated with similar potency
but a gain in lipophilicity relative to 1, leading to an erosion of
LLE (Table 2). This showed good degradation of ERα in both
a
Table 2. Phenyl B-Ring Substitution
As shown in Table 3, both compounds 8 and 9 were
exquisitely potent degraders of ERα (pIC50 > 10). This was
a
Table 3. Indazole A-Ring Substitution
ER bind
pIC50
LogD
Hu % Rat heps Hu mics
Cpd
ER DR pIC50
10.3 (99%)
10.0 (99%)
(LLE)
Free
Clint
Clint
b
8
9
9.0
3.7 (6.6)
3.6 (6.4)
6.8
5.4
10
10
44
34
ER bind
pIC50
LogD
Hu % Rat heps Hu mics
8.9
Cpd
ER DR pIC50
(LLE)
Free
Clint
Clint
a
b
Legend as Table 1. SEM 0.34.
4
5
6
7
9.3
7.8
6.3
9.7 (98%)
8.3 (95%)
8.6 (40%)
3.2 (6.5)
2.7 (5.6)
2.4 (6.2)
2.3 (4.6)
14
19
32
20
11
6
19
8
26
5
confirmed by Western blot for 9 which showed high levels of
degradation in both MCF-7 (96%) and CAMA-1 (100%) cell
lines. Lipophilicity was significantly increased in both cases, but
the LLE remained high (cf. 8 with 2 and 9 with 3).
Additionally, the effect of fluorination maintained the
permeability of 9 (Papp = 12 × 10−6 cm/s) but reduced efflux
(ER = 1.4) relative to its matched pair 3. One notable
difference was that the rat hepatocyte clearance was lowered in
both cases compared with their matched pairs in Table 1.
Unfortunately, despite the improvement in rat hepatocyte
clearance, the turnover in human microsomes was increased
for both matched pairs.
b
7.4
6.9 (>80%)
11
a
b
Legend as Table 1. SEM 0.79.
MCF-7 (98%) and CAMA-1 (97%) cell lines, comparable with
1. The 6-F (5) was weaker in terms of binding and degradation
potency. Notably this substitution reduced lipophilicity
resulting in a significant difference in lipophilicity (ΔlogD
−0.5) between the isomers 4 and 5. Methoxy (6) substitution
led to a further drop in binding and potency as well as a
reduction in the observed Dmax, resulting in a partial degrader
phenotype. The corresponding phenol (7) was weaker still in
Exemplars of a fluorinated A-ring (9) and nonfluorinated A-
ring (2) were evaluated in terms of their rat pharmacokinetic
terms of degradation but did show a more complete Dmax
.
C
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profile (Table 4). In line with the in vitro data, the clearance of
9 was significantly lower than 2 leading to an increase in both
half-life and oral bioavailability.
previously established methodology,35 alkylation of the amine
was followed by Buchwald amination with benzophenone
imine, which gave the required diamine 31 after acidic
hydrolysis. Cyclization occurred through a Pictet−Spengler
reaction with 5-bromopicolinaldehyde under slightly modified
conditions. In order to achieve reaction turnover the reaction
was performed in AcOH with H2O present as an additive.
Without the addition of H2O the initial product arose from
condensation of the free aniline onto the aldehyde. This
intermediate appeared to undergo subsequent Pictet−Spengler
cyclization very slowly; it was thus hypothesized that the
presence of a small amount of H2O would keep enough free
aniline in equilibrium to allow cyclization to occur more
readily. Pleasingly this was observed to be the case, and
diamine 31 formed the desired cyclization product after
heating with excess aldehyde. A major byproduct observed was
the desired cyclization product where the free aniline had
recondensed onto the excess aldehyde; thus, the product was
treated with NH2OH·HCl and KOAc to hydrolyze the imine
back to the free aniline. With the cyclization product in hand
the tricyclic indazole 32 was formed by treatment of the aniline
with NaNO2 in propionic acid. After the free alcohol was
oxidized to the aldehyde, the indazole was protected with a
THP group and the aldehyde was converted to difluoromethyl
by treatment with DAST. Finally, the amino-azetidine was
installed in the usual manner through Buchwald amination to
afford 11 after cleavage of the THP group.
a
Table 4. Rat Pharmacokinetic Parameters for 2 and 9
a
Clp
Vdss
IV half-
life (h)
PO AUC
(μM.h)
Bioavailability
F (%)
Cpd (mL/min/kg) (L/kg)
2
9
65
24
7.7
17
1.9
9.6
0.22
0.76
34
60
a
Compound was dosed intravenously at 0.5 mg/kg in 5%
DMSO:95% hydroxylpropyl β-cyclodextrin or 10% DMA:90%
Captisol and orally as 1 mg/kg using a 0.1% HMPC/tween
suspension or 10% DMSO:90% cyclodextrin solution. The data
shown is the mean of the data generated in two male rats.
Turning our attention to ring C, fluorination of the methyl
substituent was examined as a way to modulate the pKa of the
piperidine ring nitrogen (Scheme 5). Previously the chiral
Scheme 5. Synthesis of C-Ring Difluoromethyl Analogue
a
11
Once again, fluorination was tolerated resulting in 11 being a
subnanomolar degrader of ERα (Table 5). However, the
a
Table 5. C-Ring Substitution
a
Reagents and conditions: (a) n-BuLi, THF, DMF, then NaBH4,
MeOH, RT, 100%; (b) CBr4, PPh3, DCM, RT, 90%; (c) tert-butyl 2-
((diphenylmethylene)amino)acetate, [PTC]* (see SI for details), aq
KOH, toluene, 0 °C, 80%, 98:2 ratio of enantiomers as determined by
chiral HPLC; (d) aq HCl, EtOAc, RT, 84%; (e) LiBH4, THF, 40 °C,
100%; (f) 2,2-difluoroethyl trifluoromethanesulfonate, DIPEA, 1,4-
dioxane, RT, 91%; (g) benzophenone imine, NaOtBu, Pd2(dba)3, rac-
BINAP, toluene, 90 °C, then aq HCl, 78%; (h) 5-bromopicolinalde-
hyde, AcOH, H2O, then NH2OH·HCl, KOAc, 63%; (i) NaNO2,
propionic acid, H2O, −15 °C, 34%; (j) SO3·Py, Et3N, DCM, DMSO,
5 °C, 64%; (k) 3,4-dihydro-2H-pyran, PTSA, DCM, then DAST,
40%; (l) 1-(3-fluoropropyl)azetidin-3-amine, BrettPhos third gen-
eration precatalyst, NaOtBu, 1,4-dioxane, 70 °C, then TFA, DCM,
RT, 53%.
ER bind
pIC50
ER DR
pIC50
LogD
Hu % Rat heps Hu mics
Cpd
(LLE)
Free
Clint
Clint
10
11
8.4
8.6
9.5 (99%)
9.3 (97%)
2.4 (7.1)
2.7 (6.6)
40
28
22
32
28
34
a
Legend as Table 1.
associated rise in lipophilicity resulted in a drop in LLE relative
to 1018 and there were no beneficial effects in terms of
physicochemical parameters to justify the additional synthetic
complexity.
methyl group had been incorporated by ring-opening of the
enantiopure cyclic sulfamidate. We initially attempted to
transfer this methodology; however, we were unable to
successfully access the required difluoromethylated cyclic
sulfamidate. Instead, an asymmetric alkylation methodology
was investigated. 1,3-Dibromotoluene was treated with n-BuLi
and quenched with DMF to install the aldehyde, which was
directly reduced to the benzyl alcohol by treatment with
NaBH4. An Appel reaction then produced the required benzyl
bromide 28. Asymmetric phase-transfer catalyzed alkylation of
the glycine imine Schiff base33 with the Corey-Lygo type
cinchona alkaloid derived phase transfer catalytst34 afforded 29
in good yield and as a 98:2 ratio of enantiomers (see SI for
details). Hydrolysis of the imine and reduction of the ester
then gave the chiral amino-alcohol 30. Following our
As a final area of exploration, we turned our attention to the
alkyl chain. The concept of “motif reorganization” has been
proposed as a way to smuggle carbon atoms into fluoroalkyl
chains without adding to the lipophilic burden.36 In order to
access this substitution pattern we envisaged that a late-stage
fluorine replacement of a terminal hydroxy moiety on the alkyl
chain might be possible (Scheme 6). N-Alkylated indazole 33
was synthesized according to previously established procedures
(see SI for details). From here, Pictet−Spengler cyclization and
subsequent protection of the indazole with a THP afforded 34.
Next, the silyl protecting group was selectively cleaved and the
alcohol 35 was activated as the triflate. Treatment of the alkyl
D
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ACS Medicinal Chemistry Letters
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Letter
a
Scheme 6. Synthesis of Trifluoro Side Chain Analogue 12
AUTHOR INFORMATION
Corresponding Authors
■
James S. Scott − Oncology R&D, AstraZeneca, Cambridge CB4
0WG, United Kingdom; orcid.org/0000-0002-2263-7024;
Email: jamie.scott@astrazeneca.com
Thomas A. Moss − Oncology R&D, AstraZeneca, Cambridge
CB4 0WG, United Kingdom; Email: Thomas.Moss@
astrazeneca.com
Authors
Bernard Barlaam − Oncology R&D, AstraZeneca, Cambridge
CB4 0WG, United Kingdom; orcid.org/0000-0002-0904-
7556
Paul R. J. Davey − Oncology R&D, AstraZeneca, Cambridge
a
Reagents and conditions: (a) 5-bromopicolinaldehyde, toluene/TFA
(20:1), 110 °C, 82%; (b) 3,4-dihydro-2H-pyran, PTSA, DCM, 40 °C,
68%; (c) 1 N TBAF in THF, THF, RT, 77%; (d) Tf2O, 2,6-lutidine,
DCM; (e) 1 N TBAF in THF, THF, RT, 69% over 2 steps; (f) TFA,
DCM, RT, 82%; (g) 1-(3-fluoropropyl)azetidin-3-amine, BrettPhos
third generation precatalyst, NaOtBu, 1,4-dioxane, 60 °C, 37%.
CB4 0WG, United Kingdom
Gary Fairley − Oncology R&D, AstraZeneca, Cambridge CB4
0WG, United Kingdom
Eric T. Gangl − Oncology R&D, AstraZeneca, R&D Boston,
Waltham, Massachusetts 02451, United States
Ryan D. R. Greenwood − Oncology R&D, AstraZeneca,
Cambridge CB4 0WG, United Kingdom
Holia Hatoum-Mokdad − Oncology R&D, AstraZeneca, R&D
Boston, Waltham, Massachusetts 02451, United States
Andrew S. Lister − Oncology R&D, AstraZeneca, Cambridge
CB4 0WG, United Kingdom
David Longmire − Oncology R&D, AstraZeneca, Cambridge
CB4 0WG, United Kingdom
Radoslaw Polanski − Discovery Sciences, AstraZeneca,
Cambridge CB4 0WG, United Kingdom
triflate with TBAF smoothly formed the terminal fluoro
compound 36,37 which following deprotection of the THP
underwent Buchwald amination to afford 12.
In this case, compound 12 showed a small increase in both
potency (+0.3) and lipophilicity (+0.2) resulting in similar
LLE (6.7) relative to its trifluoromethyl matched pair 3 (Table
6). Other physicochemical properties were similar, offering no
specific advantage other than a chemical diversification option.
a
Stephen Stokes − Oncology R&D, AstraZeneca, Cambridge
CB4 0WG, United Kingdom
Table 6. CH2-Extension to Alkyl Chain
Michael J. Tucker − Oncology R&D, AstraZeneca, Cambridge
CB4 0WG, United Kingdom
Jeffrey G. Varnes − Oncology R&D, AstraZeneca, R&D Boston,
Waltham, Massachusetts 02451, United States
Bin Yang − Oncology R&D, AstraZeneca, R&D Boston,
Waltham, Massachusetts 02451, United States; orcid.org/
0000-0002-1499-5569
Complete contact information is available at:
https://pubs.acs.org/10.1021/acsmedchemlett.0c00505
ER bind
pIC50
ER DR
pIC50
LogD
(LLE)
Hu % Rat heps Hu mics
Cpd
Free
Clint
Clint
b
Author Contributions
12
8.7
9.9 (98%)
3.2 (6.7)
55
26
a
b
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Legend as Table 1. SEM 0.32.
In conclusion, we have described the incorporation of
Notes
fluorine into a drug candidate using a range of synthetic and
LSF approaches. Notably, the inclusion of fluorine was
tolerated in five of the six positions investigated, with effects
on pIC5o ranging from −0.3 to +0.6. Only one position on the
B-ring showed a large drop off in potency (ΔpIC5o −1.5). In
terms of lipophilicity, the effects on logD ranged from −0.2 to
+0.5 with most compounds retaining a high LLE. Benefits were
seen in terms of increased permeability and reduced efflux for
one example (2) and lower rat clearance and higher
bioavailability for another (9).
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The Analytical and Purification teams at AstraZeneca are
thanked for their contributions. Matt Leese, Tom Heightman,
Nicky Whalley, and Ray Finlay are thanked for their valuable
contributions regarding the manuscript.
ABBREVIATIONS
■
BINAP, ( )-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene;
Bpin, pinacolatoboron; Brettphos, 2-(dicyclohexylphosphino)-
3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl; Clp, plasma
clearance; DAST, (diethylamino)sulfur trifluoride; dba,
dibenzylideneacetone; ER, efflux ratio; ERα, estrogen receptor
α; LLE, ligand lipophilic efficiency; LSF, late stage
functionalization; Papp, apparent permeability; PTSA, para-
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acsmedchemlett.0c00505.
■
sı
Data tables, experimental procedures, and character-
ization data (PDF)
E
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ACS Medicinal Chemistry Letters
pubs.acs.org/acsmedchemlett
Letter
Huynh, H.; Janbon, S. L. M.; Johnson, J.; Kavanagh, S.; Klinowska, T.;
Lawson, M.; Lister, A. S.; Marden, S.; McGinnity, D. F.; Morrow, C.
J.; Nissink, J. W. M.; O’Donovan, D. H.; Peng, B.; Polanski, R.; Stead,
D. S.; Stokes, S.; Thakur, K.; Throner, S. R.; Tucker, M. J.; Varnes, J.;
Wang, H.; Wilson, D. M.; Wu, D.; Wu, Y.; Yang, B.; Yang, W.
Discovery of AZD9833, a potent and orally bioavailable selective
estrogen receptor degrader and antagonist. J. Med. Chem. 2020,
DOI: 10.1021/acs.jmedchem.0c01163.
(19) Fier, P. S.; Hartwig, J. F. Synthesis and Late-Stage
Functionalization of Complex Molecules through C−H Fluorination
and Nucleophilic Aromatic Substitution. J. Am. Chem. Soc. 2014, 136,
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(21) Degradation of ER was measured relative to fulvestrant (Fv) in
MCF-7 and CAMA-1 cells as determined by Western blot at 0.1 μM.
For 1 the degradation was measured as 95% and 98%, respectively.
For 2 the corresponding values are 93% and 106%, and for 3 they are
96% and 98%, respectively. For full details see the Supporting
Information.
toluene sulfonic acid; r.t., room temperature; SAR, structure−
activity relationship; Selectfluor, 1-chloromethyl-4-fluoro-1,4-
diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate); SERD,
selective estrogen receptor degrader; Vdss, steady-state volume
of distribution
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