Discovery of ABBV/GLPG-3221, a Potent Corrector of CFTR for the Treatment of Cystic Fibrosis

Article abstract of DOI:10.1021/acsmedchemlett.9b00377

Cystic fibrosis (CF) is a genetic disorder that affects multiple tissues and organs. CF is caused by mutations in the CFTR gene, resulting in insufficient or impaired cystic fibrosis transmembrane conductance regulator (CFTR) protein. The deletion of phenylalanine at position 508 of the protein (F508del-CFTR) is the most common mutation observed in CF patients. The most effective treatments of these patients employ two CFTR modulator classes, correctors and potentiators. CFTR correctors increase protein levels at the cell surface; CFTR potentiators enable the functional opening of CFTR channels at the cell surface. Triple-combination therapies utilize two distinct corrector molecules (C1 and C2) to further improve the overall efficacy. We identified the need to develop a C2 corrector series that had the potential to be used in conjunction with our existing C1 corrector series and provide robust clinical efficacy for CF patients. The identification of a pyrrolidine series of CFTR C2 correctors and the structure-activity relationship of this series is described. This work resulted in the discovery and selection of (2S,3R,4S,5S)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylic acid (ABBV/GLPG-3221), which was advanced to clinical trials.

Full text of DOI:10.1021/acsmedchemlett.9b00377

Letter
pubs.acs.org/acsmedchemlett
Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
Discovery of ABBV/GLPG-3221, a Potent Corrector of CFTR for the
Treatment of Cystic Fibrosis
Marc J. C. Scanio,* Xenia B. Searle, Bo Liu, John R. Koenig, Robert Altenbach, Gregory A. Gfesser,
Andrew Bogdan, Stephen Greszler, Gang Zhao, Ashvani Singh, Yihong Fan, Andrew M. Swensen,
Timothy Vortherms, Arlene Manelli, Corina Balut, Ying Jia, Wenqing Gao, Hong Yong,
Michael Schrimpf, Chris Tse, Philip Kym, and Xueqing Wang
Research and Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States
*
S Supporting Information
ABSTRACT: Cystic fibrosis (CF) is a genetic disorder that
affects multiple tissues and organs. CF is caused by mutations
in the CFTR gene, resulting in insufficient or impaired cystic
fibrosis transmembrane conductance regulator (CFTR)
protein. The deletion of phenylalanine at position 508 of
the protein (F508del-CFTR) is the most common mutation
observed in CF patients. The most effective treatments of
these patients employ two CFTR modulator classes, correctors
and potentiators. CFTR correctors increase protein levels at
the cell surface; CFTR potentiators enable the functional opening of CFTR channels at the cell surface. Triple-combination
therapies utilize two distinct corrector molecules (C1 and C2) to further improve the overall efficacy. We identified the need to
develop a C2 corrector series that had the potential to be used in conjunction with our existing C1 corrector series and provide
robust clinical efficacy for CF patients. The identification of a pyrrolidine series of CFTR C2 correctors and the structure−
activity relationship of this series is described. This work resulted in the discovery and selection of (2S,3R,4S,5S)-3-(tert-butyl)-
4
-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-car-
boxylic acid (ABBV/GLPG-3221), which was advanced to clinical trials.
KEYWORDS: Cystic fibrosis, ABBV/GLPG-3221, cystic fibrosis transmembrane conductance regulator protein (CFTR)
ystic fibrosis (CF) is a genetic disorder that affects
multiple tissues and organs. CF impacts more than
channel function in the lungs results in the buildup of a thick
mucus that leads to bacterial colonization, resulting in the loss
of lung function in CF patients. The loss of this lung function
is the leading cause of death in these CF patients. These
patients are also affected by potentially life-threatening
pancreatic insufficiency and gastrointestinal issues.
C
Over 2000 single nucleotide polymorphisms (SNPs) have
been identified in the CFTR protein of CF patients, 336 of
3
which are disease-causing. The complications that result from
these mutations fall into six classes affecting the stability,
4
function, trafficking, or production of CFTR. The deletion of
phenylalanine at position 508 of the protein (F508del-CFTR)
is the most common mutation observed in CF patients.
Approximately 85% of CF patients have at least one copy of
the F508del-CFTR allele, and the homozygous F508del-CFTR
mutation is observed in ∼50% of CF cases. This deletion
prevents the nascent protein from folding correctly and
translocating to the plasma membrane for normal anion
Figure 1. Structures of previously reported CFTR C1 corrector
compounds.
1
7
0 000 people worldwide. It is caused by mutations in the
5
,6
transport. As a result, far fewer F508del-CFTR channels are
expressed on the cell membrane compared with wild-type
CFTR gene, resulting in insufficient or impaired cystic fibrosis
2
transmembrane conductance regulator (CFTR) protein.
CFTR is an anion channel that is capable of transporting
−
−
both Cl and HCO and is expressed in many epithelial cells.
Received: August 12, 2019
Accepted: October 28, 2019
3
It is also responsible for regulating the balance of water and salt
in multiple tissues. The impairment of the normal CFTR
©
XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.9b00377
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Letter
Table 1. CSE-HRP SAR for the Initial Series Hits
Table 2. HBE-TECC SAR for Ether Analogs 7−10
a
HBE-TECC assay was run using ABBV-2222 (0.15 μM) and
GLPG1837 (0.75 μM) as the positive controls. All values are the
geometric means of at least two determinations.
potentiators enable the functional opening of CFTR channels
at the cell surface. Dual-combination therapies such as
11−14
Orkambi and Symdeko have been approved,
restoring
lung function to a modest degree in F508del homozygous
patients. Triple combinations utilizing two distinct corrector
molecules and a potentiator molecule have demonstrated
transformational clinical benefit in patients with a F508del-
15−18
CFTR mutation on at least one allele.
A New Drug
Application has recently been filed to the FDA for one such
19,14
triple combination.
However, how universal this will be
across the multitude of genotypes remains to be assessed.
Herein we report the identification of a pyrrolidine series of
CFTR C2 correctors and the structure−activity relationship
(
3
SAR) of this series, which leads to the identification of ABBV-
221 (also known as GLPG-3221). This CFTR C2 corrector
has been advanced to clinical trials.
We have previously reported a novel series of CFTR C1
20
corrector compounds, including ABBV-2222 (Figure 1),
which are currently in clinical trials in CF patients. These C1
correctors restore the early folding process of the protein to
increase the number of CFTR channels expressed on the cell
membrane. C2 correctors work by any complementary
mechanism to further increase CFTR at the cell surface. In
an effort to develop a CF triple therapy, we initiated efforts to
develop a CFTR C2 corrector.
a
CSE-HPR assay was run using compound 1 (3 μM) as the positive
control. All values are the geometric means of at least two
determinations. This format of the CSE-HPR assay was run with
compound 1 (3 μM) as a C1 corrector and as the positive control. All
values are the geometric means of at least two determinations.
b
15
Two cell-based assays were employed to determine the
activity of CFTR modulators. CFTR correctors are a class of
modulators that correct the misfolding mutant CFTR protein,
increasing the CFTR channel expression on the cell surface.
The CFTR expression was quantified using immortalized
7
CFTR (WT-CFTR)-expressing cells. Furthermore, F508del-
CFTR channels are less effective at channel gating compared
with WT-CFTR. The most effective treatments of these
patients employ two CFTR modulator classes. CFTR
correctors increase protein levels at the cell surface; CFTR
8
9
1
0
21
bronchial epithelial cells (CFBE41o) transduced with
B
DOI: 10.1021/acsmedchemlett.9b00377
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ACS Medicinal Chemistry Letters
Letter
Table 3. HBE-TECC and CYP3A4 Induction SAR for N1
Analogs 8 and 11−13
Table 4. HBE-TECC and CYP3A4 Induction SAR for
Aromatic Analogs 10 and 12−17
a
HBE-TECC assay was using ABBV-2222 (0.15 μM) and GLPG1837
(
0.75 μM) as the positive controls. All values are the geometric means
b
of at least two determinations. All values are the means of at least
three determinations.
F508del-CFTR fused with horseradish peroxidase (HRP). See
the Supporting Information for experimental details. Test
corrector compounds were incubated with or without a
cocorrector, 2 μM of compound 1, overnight, followed by
the measurement of the HRP activity to detect matured
F508del-CFTR levels. This CSE-HRP (cell surface ex-
pression−HRP) assay was used for primary high-throughput
screens (HTSs) and as a primary assay for driving the
medicinal chemistry efforts.
a
22
HBE-TECC assay using ABBV-2222 (0.15 μM) and GLPG1837
(0.75 μM) as the positive controls. All values are the geometric means
b
of at least two determinations. All values are the means of at least
three determinations.
The objective of this research is to increase the membrane
expression and improve the stability and function of the
corrected F508del-CFTR channels. We measured the function
of the channels using a HBE-TECC (human bronchial
epithelial−transepithelial current clamp) assay. Primary
human bronchial epithelial (HBE) cells from F508del CF
patients were used, and an electrophysiology (E-Phys)
measurement of the CFTR chloride ion current across the
apical membrane was taken. See the Supporting Information
for experimental details. In brief, the assay uses a transepithelial
desired compound profile would improve the cell surface
expression with and without cocorrector 1 present. Compound
2, a pentasubstituted pyrrolidine, was identified as a potential
hit. It had an average EC50 of 2.72 μM, with a maximum
response of 186% relative to compound 1 alone (Table 1). In
the presence of 1, compound 2 had an average EC50 of 2.11
μM, with a maximum response of 681% relative to compound
1 (Table 1). To confirm the potency of this hit, the CSE-HRP
assay was repeated four times with and without compound 1 as
a C1 corrector. This resulted in an EC range of 2.3 to 3.2 μM
23
current clamp (TECC) instrument to measure the function
of the F508del-CFTR channel after the overnight incubation of
the test corrector compounds in the presence of a
5
0
alone and an EC50 range of 1.7 to 2.7 μM in the presence of
compound 1.
2
4
potentiator and cocorrector and activated with forskolin.
The assay uses negative and positive controls (0.15 μM of
ABBV-2222) to measure the correction of the mutated CFTR
The exact stereochemistry of 2 was not specified at the time
of registration in 1982, and the compound was clearly a
mixture of diastereomers. One of the diastereomers of 2 was
synthesized and isolated as a racemic mixture, compound 3. It
had an average EC50 of 2.66 μM (151%) and an average EC50
of 1.97 μM (527%) in the presence of compound 1 (Table 1).
This key hit compound was used as a positive control in the
2
5
channel.
An HTS was conducted, with the objective of identifying
compounds that could serve as hits for the development of a
CFTR C2 corrector series using the CSE-HRP assay. The
C
DOI: 10.1021/acsmedchemlett.9b00377
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ACS Medicinal Chemistry Letters
Letter
a
Table 5. Pharmacokinetic Properties of 19 in Rat and Dog
IV dose
oral dose
b
c
Cl
t1/2
F (%)
rat PK
dog PK
0.13
0.64
3.0
6.4
53
78
a
b
Parameters were determined using a 1 mg/kg dose. Clearance (L/
c
h/kg). Half life (h).
CSE-HRP assay and was tested over 300 times with and
without cocorrector 1. In an effort to improve the properties of
3
compound 3, by increasing the fraction of sp -hybridized
carbons (Fsp3), the phenyl group of the N-benzoyl moiety was
replaced with a cyclohexane, resulting in compound 4. This
compound had comparable potency, with greatly improved
efficacy in the CSE assay. The ketone moiety of compounds
2
−4 was flagged for replacement. Moving from the ketone in 4
to the benzyl ether in 5 increased the Fsp3 and removed any
issues of reactivity associated with the acetophenone group.
26
Figure 2. Dose−response graph for 19 in triple combination format.
The data are a combination from two separate experiments run on
different days with cells from one CF donor with homozygous
F508delCFTR mutation, with n = 3 replicates at each concentration.
Compound 5 maintained reasonable potency. The individual
enantiomers of 5 were isolated by chiral preparative super-
critical fluid chromatograpy (SFC) to afford enantiomers 6 and
7
. The majority of the potency and the efficacy of 5 clearly
resides in the (2S,3R,4S,5S)-isomer, 7 (Table 1). Running the
CSE-HRP assay in the presence of C1 corrector, 1, made the
EC slightly more potent while greatly improving the efficacy.
a
Scheme 1. Discovery Synthesis of ABBV/GLPG-3221 (19)
5
0
On the basis of the data presented in Table 1, we decided to
focus our efforts on benzyl ether analogs with the
(
2S,3R,4S,5S) stereochemistry, analogs to compound 7.
Compound 7 was thus identified as submicromolar in the
CSE-HRP assay and was then advanced to testing in human
bronchial epithelial (HBE) cells and evaluated in the TECC
assay. It showed good potency (173 nM) and efficacy (590%)
relative to the positive control, ABBV-2222 (0.15 μM) in the
presence of potentiator GLPG1837 (0.75 μM) (Table 2).
Initially, we chose to evaluate the SAR of the benzyl ether
portion of this series (Table 2). The cLogP of compound 7 is
6
.01, and we were interested in introducing a heteroatom into
the aromatic ring of 7, such as that found in pyridine 8. The
cLogP of compound 8 was reduced to 5.27, and the compound
had improved potency in the HBE-TECC assay (150 nM,
6
50%) (Table 2). Replacing the trifluoromethyl group of
compound 8 with a cyclopentane or a tert-butyl group led to
compounds that were both less potent and had higher cLogP
values (5.95, 9; 6.12, 10).
The further interrogation of compound 8 indicated that it is
a CYP3A4 inducer in an induction assay compared with the
positive control rifampin (Table 3). In this assay (Supporting
Information), the compound is tested at 10 or 1 μM in
triplicate, and the response is compared with that of 10 μM
rifampin, a CYP3A4 inducer. Compounds with a response of
<
20% of rifampin at 10 μM are considered to have a low
a
Reagents and conditions: (a) MgSO , TEA, 2-methylbenzaldehyde,
induction risk. Compound 8 had a response of 74% at 10 μM.
Analogs of compound 8 were synthesized that differed in the
substitution off of the pyrrolidine nitrogen. Switching from the
cyclohexanecarboxamide of 8, to the isopropyl carbamate
found in 11 led to a compound that was slightly more potent
but less efficacious and, very importantly, not a CYP3A4
inducer (Table 3). The diastereomeric pyran compounds 12
and 13 were prepared as direct analogs of compound 8. The
4
DCM; (b) (2-(bis(3,5-bis(trifluoromethyl)phenyl)phosphino)-3-
(
(
(S)-4-isopropyl-4,5-dihydrooxazol-2-yl)cyclopenta-2,4-dien-1-yl)-
cyclopenta-2,4-dien-1-yl)iron, Cu(OTf) , KOtBu, (E)-3,3-dimethyl-
2
1
-nitrobut-1-ene, THF; (c) allyl chloroformate, toluene; (d) PDC, 6
N HCl, Zn dust; (e) NaBH , EtOH; (f) KOtBu, 3-(bromomethyl)-2-
4
methoxy-5-(trifluoromethyl)pyridine, DMF; (g) 1,3-dimethlbarbituric
acid, Pd(PPh ) , EtOAc/DCM; (h) tetrahydropyran-2-carboxylic
acid, oxalyl chloride, DMF, DCM; and (i) LiOH, MeOH/THF.
3
4
(
S)-pyran analog 12 was more potent and much more
efficacious than the (R)-pyran analog 13. Compound 12 was
advanced to the CYP3A4 induction assay, where it did not
D
DOI: 10.1021/acsmedchemlett.9b00377
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ACS Medicinal Chemistry Letters
Letter
induce CYP3A4 (Table 3). Compared with cyclohexane 8,
pyran 12 was somewhat less potent (213 vs 150 nM), but
more efficacious (720 vs 650%).
Because of the improvement in CYP3A4 induction, we
focused on optimizing compounds with the (S)-pyran
substitution. These analogs varied the aromatic group off the
C5 position of the pyrrolidine ring (Table 4). The introduction
of large alkyl groups at the ortho position of the aromatic ring
improvement over a dual combination of GLPG-1837 and
ABBV-2222 when used as a triple combination in in vitro
studies; therefore, it was selected to advance into clinical trials
to evaluate its potential for treating cystic fibrosis.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsmedchem-
lett.9b00377.
■
*
S
(
compounds 14, 15, 17, and 18) led to a dramatic
improvement in potency (35−66 vs 213 nM, compound 12)
while maintaining reasonable efficacy. All of these compounds
were, however, potent CYP3A4 inducers whether they were
tested at 1 or 10 μM. Chloro substitution at the ortho position
Synthetic procedures and compound characterization
data for ether compounds 5−19 and intermediates as
well as assay procedures (PDF)
(16) afforded a compound that did not show induction at 1
μM but did not have the desired potency (Table 4). Finally,
the substitution of a methyl group at the ortho position
resulted in a compound with good balance of characteristics
AUTHOR INFORMATION
Corresponding Author
*Phone: +1-847-935-1064. E-mail: marc.scanio@abbvie.com.
■
(
Compound 19, Table 4). Whereas compound 19 was
somewhat less potent than compounds with a larger alkyl
substitution, it still had an EC50 = 105 nM and, importantly,
was not found to have a high CYP3A4 induction risk (Table
ORCID
Marc J. C. Scanio: 0000-0002-3503-8020
Andrew Bogdan: 0000-0003-0913-0779
Stephen Greszler: 0000-0003-1993-2417
4
).
The detailed dose response HBE-TECC data for compound
9 are shown in Figure 2. The 100% response is set by the
Author Contributions
1
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
combination of ABBV-2222 (0.15 μM) and GLPG1837 (0.75
μM). The addition of compound 19 to the combination of
ABBV-2222 and GLPG1837 increased the CFTR current with
EC50 = 105 nM and a maximum response of 585% compared
with the double combination alone.
Funding
The design, study conduct, and financial support for this
research were provided by AbbVie and Galapagos.
Notes
The authors declare the following competing financial
interest(s): All authors are current AbbVie employees.
Compound 19 was selected for advancement into additional
characterization. An optimized discovery scale synthesis is
illustrated in Scheme 1. Commercially available glycine ethyl
ester hydrochloride (20) was condensed with 2-methylbenzal-
dehyde to afford imine 21. An enantioselective [3 + 2]
cycloaddition was an ideal method to forge the stereogenic
pyrrolidine core (22) from imine 21 and (E)-3,3-dimethyl-1-
ACKNOWLEDGMENTS
We acknowledge Clinton Yeung for the preparation of
intermediate compounds.
■
2
7
nitrobut-1-ene. This was achieved using a Cu-catalyzed
enantioselective cycloaddition catalyzed by a Cu(I)/(2-(bis-
(
3,5-bis(trifluoromethyl)phenyl)phosphino)-3-((S)-4-isoprop-
yl-4,5-dihydrooxazol-2-yl)cyclopenta-2,4-dien-1-yl)-
cyclopenta-2,4-dien-1-yl)iron complex. Reacting pyrrolidine
2 with allyl chloroformate gave the Alloc-protected
ABBREVIATIONS
■
Alloc, allyloxycarbonyl; CF, cystic fibrosis; CFTR, cystic
fibrosis transmembrane conductance regulator protein; CSE-
HRP, cell surface expression−horseradish peroxidase;
CYP3A4, cytochrome P450 3A4; DCM, dichloromethane;
DDI, drug−drug interaction; DMF, dimethylformamide;
DMSO, dimethyl sulfoxide; E-Phys, electrophysiology; Emax,
maximum percent activity; ER, endoplasmic reticulum; FEV ,
forced expiratory volume in 1 s; Fsp3, sp -hybridized carbons;
HBE, human bronchial epithelial; HBE-TECC, human
(
2
intermediate 23. A Nef reaction converted the nitro moiety
of compound 23 into the ketone of 24. Sodium borohydride in
ethanol gave the selective reduction of the ketone to alcohol
2
5. The alkylation of alcohol 25 with 3-(bromomethyl)-2-
1
methoxy-5-(trifluoromethyl)pyridine using potassium tert-
butoxide as the base in dimethylformamide (DMF) generated
ether 26. The Alloc group of 26 was removed with catalytic Pd
to afford the NH pyrrolidine 27 that was readily acylated with
the acid chloride generated in situ from tetrahydropyran-2-
carboxylic acid to yield ester 28. The ester was saponified to
the acid using lithium hydroxide in MeOH/THF to afford
compound 19, ABBV-3221. Optimizations required for a
3
bronchial epithelial−transepithelial current clamp; HRP,
horseradish peroxidase; HTS, high-throughput screen; I ,
EQ
equivalent CFTR current; PDC, potassium dichromate; PK,
pharmacokinetic; SAR, structure−activity relationship; SNPs,
single nucleotide polymorphisms; SFC, supercritical fluid
chromatography; TEA, triethylamine; TECC, transepithelial
current clamp; THF, tetrahydrofuran; WT-CFTR, wild-type
CFTR
28
multikilogram scale process will be reported.
Compound 19 was also found to have a good
pharmacokinetic (PK) profile in both rats and dogs, which is
summarized in Table 5.
On the basis of the data presented here, along with
additional preclinical safety evaluations, compound 19 (ABBV-
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DOI: 10.1021/acsmedchemlett.9b00377
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX