Discovery of CYR715: A novel carboxylic acid-containing soluble guanylate cyclase stimulator

Article abstract of DOI:10.1016/j.bmcl.2021.127886

Soluble guanylate cyclase (sGC) is a clinically validated therapeutic target in the treatment of pulmonary hypertension. Modulators of sGC have the potential to treat diseases that are affected by dysregulation of the NO-sGC-cGMP signal transduction pathw

Full text of DOI:10.1016/j.bmcl.2021.127886

Bioorg. Med. Chem. Lett. 40 (2021) 127886
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of CYR715: A novel carboxylic acid-containing soluble guanylate
cyclase stimulator
Glen R. Rennie1, Timothy C. Barden, Sylvie G. Bernier, Andrew Carvalho, Renee Deming,
Peter Germano, Colleen Hudson, G-Yoon J. Im, Rajesh R. Iyengar, Lei Jia, Joon Jung, Elise Kim,
Thomas W.-H. Lee1, Ara Mermerian, Joel Moore, Takashi Nakai, Nicholas R. Perl, Jenny Tobin,
,
1
Daniel P. Zimmer, Paul A. Renhowe*
Cyclerion Therapeutics, Inc., 301 Binney Street Cambridge, MA 02142, United States
A R T I C L E I N F O
A B S T R A C T
Keywords:
Soluble guanylate cyclase (sGC) is a clinically validated therapeutic target in the treatment of pulmonary hy-
pertension. Modulators of sGC have the potential to treat diseases that are affected by dysregulation of the NO-
sGC-cGMP signal transduction pathway. This letter describes the SAR efforts that led to the discovery of CYR715,
a novel carboxylic acid-containing sGC stimulator, with an improved metabolic profile relative to our previously
described stimulator, IWP-051. CYR715 addressed potential idiosyncratic drug toxicity (IDT) liabilities associ-
ated with the formation of reactive, migrating acyl glucuronides (AG) found in related carboxylic acid-containing
analogs and demonstrated high oral bioavailability in rat and dose-dependent hemodynamic pharmacology in
normotensive Sprague–Dawley rats.
Soluble guanylate cyclase
sGC
sGC stimulator
Nitric oxide
CYR715
Soluble guanylate cyclase (sGC) is a heterodimeric intracellular
enzyme that plays a key role in the nitric oxide (NO)-sGC-cyclic
guanosine-monophosphate (cGMP) cell signaling pathway. Its primary
function is to convert guanosine-5′-triphosphate (GTP) to the secondary
messenger cGMP in response to NO. Activation of sGC occurs after
binding of the endogenous ligand NO to the prosthetic heme located
within the β1 subunit. More specifically, NO binds to the Fe2+ of the
heme in the H-NOX domain, which induces a conformational change in
the distal catalytic domain of the enzyme, leading to formation of
cGMP.1,2 Signal transduction mediated by cGMP, through cGMP-
dependent protein kinase (PKG), phosphodiesterases (PDEs) & cyclic
nucleotide-gated ion channels, contributes to the regulation of vaso-
Oxidized sGC primarily exists in conditions of oxidative stress and is
incapable of binding NO. Two distinct compound classes are known to
interact with sGC, heme-dependent stimulators and heme-independent
activators (Fig. 1).8,9 sGC stimulators, e.g. IWP-0513,10 and rioci-
guat,11,12 are small-molecule agonists that have been proposed to bind
within an allosteric site adjacent to the heme group of the reduced form
of sGC and synergize with NO to activate the enzyme.13 sGC activators,
e.g., cinaciguat, bind in place of the heme group and activate the enzyme
without requiring NO.14–15 sGC activators contain at least one carbox-
ylic acid that mimics a pendant acid anchoring the prosthetic heme
group within the heme-binding pocket of sGC.16–18 To date, one sGC
stimulator has been approved for clinical use (Fig. 1. riociguat, taken
three times each day, is approved for the treatment of pulmonary arte-
rial hypertension and chronic thromboembolic pulmonary hyperten-
sion) and several others are in (early to late) clinical development.
Clinical investigation of the sGC activator cinaciguat for treatment of
acute heart failure was discontinued due to dose-limiting hypotension.19
relaxation,
inflammation,
fibrosis,
metabolism,
and
neurotransmission.3–7
sGC can exist in at least two forms: the reduced form in which the
Fe2+ heme group is present, and the oxidized form in which Fe2+ has
been oxidized to Fe3+, which can result in the loss of the heme group.
Abbreviations: sGC, soluble guanylate cyclase; DETA-NO, diethylenetriamine NONOate; AUC, area under the curve; RLM, rat liver microsome; HLM, human liver
microsome; MAP, mean arterial pressure; SAR, structure–activity relationship; TEA, triethyl amine; NaH, sodium hydride; THF, tetrahydrofuran; SNAr, nucleophilic
aromatic substitution; POCl3, phosphorus(V) oxide chloride; AG, acyl glucuronide conjugate; IDT, idiosyncratic drug toxicity; ODQ, 1H-[1,2,4]oxadiazolo[4,3-a]
quinoxalin-1-one; CYP, cytochrome P450 isoenzymes.
* Corresponding author.
E-mail address: prenhowe@gmail.com (P.A. Renhowe).
1
Authors contributed equally.
https://doi.org/10.1016/j.bmcl.2021.127886
Received 10 September 2020; Received in revised form 9 February 2021; Accepted 10 February 2021
Available online 2 March 2021
0960-894X/© 2021 Elsevier Ltd. All rights reserved.

G.R. Rennie et al.
Bioorganic & Medicinal Chemistry Letters 40 (2021) 127886
Fig. 1. Examples of sGC agonists.
Table 1
Early SAR exploration.
Compound
R
sGC EC50 [nM]a
RLM CLbint
cLogPc
IWP-051
97
6
2.4
2.4
3.0
2
3
420
2300
95
450
Fig. 2. Overlay of IWP-051 (green) and riociguat (magenta).
4
4400
460
1.9
5
6
130
20
17
2.4
2.8
160
7
41
320
2.1
8
9
83
27
500
490
3.1
3.6
Scheme 1. Synthesis of Compoundsa. aRepresentative conditions: (a) neat
POCl3, 100 ℃; (b) amine, TEA, dioxane/water, 100 ℃; (c) alcohol, NaH, THF,
23 ℃.
aCellular potency measured in cGMP GloSensor® assay in the presence of 10 µM
DETA-NO based on geometric mean of at least two experiments. b Intrinsic he-
patic clearance (µL/min/mg protein); RLM = rat liver microsomes. c Calculated
LogP determined by ACDlabs v14.04 software.
We previously reported the discovery of IWP-051, an sGC stimulator
derived from our lead generation effort to design stimulators from a new
chemotype with once-daily dosing potential in humans.10 IWP-051 be-
longs to a novel class of sGC stimulators that feature a biaryl pyrazole
structure unlike the fused ring pyrazolo[3,4-b]pyridine core shared by
BAY 41-2272 and riociguat. IWP-051 possesses many favorable attri-
butes as demonstrated in several PK and PD preclinical animal studies.
In a cell-based assay, IWP-051 demonstrated potent NO-dependent sGC
activity (EC50 = 97 nM). In rat, the clearance of IWP-051 was low (CL =
0.6 mL/min/kg), the half-life was 4.1 h, and the bioavailability was high
(Fpo = 96%). In a multi-dose rat PK study (data not shown), evidence of
potential accumulation of IWP-051 was observed.27 In this letter, we
describe the design and optimization of IWP-051 analogs with the goal
of producing a more desirable pharmacokinetic profile predictive of
once-daily dosing in humans without accumulation potential.
desired potency, fine-tune physicochemical properties and improve the
PK profile of this chemical series.
While keeping the pyrazole substituents unchanged, we substituted
the pyrimidine C(4) position using standard SNAr chemistry. The general
synthesis is outlined in Scheme 1. Conversion of IWP-051 to chloro-
pyrimidine (1) using POCl3 was achieved under standard conditions.
4-Amino substituted analogs were obtained by treatment of 1 with
amines under basic conditions while 4-alkoxy substituted analogs were
synthesized using pre-formed sodium alkoxides.
The initial SAR is shown in Table 1. Methylation of the oxygen (2)
lowered both potency and metabolic stability; increasing the O-alkyl
chain size (3 and 4) was even less favorable. In addition, the potential O-
dealkylation of any ether side chain in vivo could possibly liberate IWP-
051 as a stable, active metabolite. Hence, ethers were abandoned in
favor of C(4)-amino substituents (5–9) with different physicochemical
properties.
To initiate our SAR effort, we developed a ligand-based 3D phar-
macophore model based on internally discovered and published sGC
stimulators. Comparing the overlay of IWP-051 with riociguat (Fig. 2),
we observed a vectoral overlap of the IWP-051C(4)–OH with the rioci-
guat C(5)-N-methyl carbamate.11,12 For the 4/5-position overlap to
exist, the model predicted a slight shift in alignment of the major axes of
the two molecules in order to preserve maximum overlay between the
hydrogen bond acceptor nitrogen of the isoxazole and pyridine, and the
2-F-phenyl moieties of the two molecular cores. With these insights, we
hypothesized that the substitution of C(4) could be used to achieve
Amines 6 – 9 showed promising potency but poor metabolic stability.
We conducted an in vitro metabolite ID study of 9 to determine the
location of metabolism. Our analysis showed that the piperidine moiety
was subject to phase I oxidation via hydroxylation of the electron-rich
alpha carbon. Further oxidation and N-dealkylation resulted in 5 as
2

G.R. Rennie et al.
Bioorganic & Medicinal Chemistry Letters 40 (2021) 127886
Table 3
SAR of acid analogs.
Scheme 2. Human liver microsome phase I metabolism of 9.
Compound
19
R
sGC EC50
[nM]a
RLM
CLbint
AG Formed, Migrated
/ Ratec
970
ND
ND
Table 2
(rac)-20
2300
8
ND
Metabolic blocking strategies.
21
7
22
29
29
+, + / 22
+, + / 24
+, + / 3
(rac)-22
23
55
120
Compound
10
R
sGC EC50 [nM]a
150
RLM CLbint
490
cLogPc
3.2
11
250
340
3.2
24
200
1340
33
14
71
24
32
+, + / 5
ND
(rac)-12
13
33
10
35
360
390
460
2.5
2.5
2.8
(rac)-25
26
(rac)-14
+, + / 1
+, + / 1
15
16
240
66
1.4
2.5
27
40
(CYR715)
1300
160
aCellular potency measured in cGMP GloSensor® assay in the presence of 10 µM
DETA-NO based on geometric mean of at least two experiments. b CLint (µL/min/
mg protein) in microsomes; RLM = rat liver microsomes; AG = acyl glucuronide
17
18
50
260
72
2.5
2.3
c
conjugate, ND = not determined. + = observed; Rate is expressed as %
120
migrated after 90 min. incubation.
aCellular potency measured in cGMP GloSensor® assay in the presence of 10 µM
DETA-NO based on geometric mean of at least two experiments. b CLint (µL/min/
mg protein); RLM = rat liver microsomes; ND = not determined. c Calculated
LogP determined by ACDlabs v14.04 software.
051 as determined by incubation with rat liver microsomes.
Glucuronidation can contribute to the metabolic clearance for car-
boxylic acid-bearing drugs.22 Upon glucuronidation of the acid moiety,
the resulting acyl glucuronide conjugate (AG) can migrate and behave as
a reactive metabolite, potentially reacting covalently with proteins and
other biomolecules, which can subsequently lead to idiosyncratic drug
toxicity (IDT).23 In order to minimize the risk of potential drug-related
adverse events due to reactive acyl glucuronides, we incorporated an
in vitro AG reactivity assay as part of our testing funnel to assist with the
selection of low-risk molecules.24
the major metabolite (Scheme 2).
Efforts to improve the stability by leveraging the inductive effect of
fluorine (Table 2, 10 and 11) were not fruitful. This result is likely due to
a concomitant increase in lipophilicity.20 An alternative approach was
taken to improve metabolic stability by lowering cLogP. Hydroxylated
analogs (12, 13 and 14) did not significantly improve metabolic sta-
bility; however, they were considerably more potent than 9. Additional
analogs (15 – 18) were investigated and gave the first signs of
improvement in metabolic stability. Encouraged by this result, we
decided to further explore more polar substituents.
Although each carboxylic acid analog tested in human liver micro-
somes formed the 1-β-O-acyl glucuronide (1-β-O-AG), as confirmed by
β-glucuronidase hydrolysis, different degrees of migration to either the
2, 3, or 4-β-O-AG isomers, and clear SAR trends were observed with
migration rate – the primary measure of intrinsic chemical stability of
the acyl glucuronide conjugate. Using migration rate as a measure of AG
reactivity, we sought to select compounds with rates less than 20% as
this cut-off correlates well with the AG half-life of approved drugs
known to have a low risk for IDT.24
A common approach to reducing lipophilicity is to introduce car-
boxylic acid functionality. The ionic character can disfavor substrate
recognition by the generally hydrophobic binding site of the cytochrome
P450 enzymes.21 The data summarized in Table 3 highlight the im-
provements to CLint by the introduction of carboxylic acids around the
cyclic amino groups (19 – 27). Initial substitution for carboxylic acids
showed, for the first time, favorable potency and metabolic stability
(21–24) compared to 9, though substitution was not tolerated on other
cyclic amines (19, 20). In all cases in which carboxylic acids were pre-
sent, in vitro clearance was reduced and was now comparable to IWP-
As shown in Table 3, our piperidine acid analogs such as 21 had a
migration rate of 22%, which did not meet the risk cut-off. Similarly,
while 22 was potent and stable, it did not meet our cut-off with a
migration rate of 24%. However, when the acid was located at the 2-po-
sition of piperidine (23 and 24), the migration rate was diminished >4-
fold compared to the 3- and 4-position. We hypothesized that further
3

G.R. Rennie et al.
Bioorganic & Medicinal Chemistry Letters 40 (2021) 127886
idiosyncratic drug toxicity risk. In addition, when CYR715 and 26 were
tested for relevant inhibition of major human CYP isoforms (3A4, 2D6,
2C9, 1A2, 2C19, 2C8), only 26 inhibited 2C9 (IC50 = 3.2 μM). As a
result, compound CYR715 was prioritized for further rat pharmacoki-
netic studies.
When compared to IWP-051 (Table 4), the solubility and cell
permeability of CYR715 were higher and the intrinsic clearance in
human liver microsomes (HLM) was more favorable. In rat PK studies,
we were pleased to observe high oral bioavailabilty, a similar half-life,
and improved hepatic clearance in line with our goal of attenuating
the metabolic stability of IWP-051 to reduce the risk of accumulation.27
CYR715 was evaluated for pharmacodynamic effects in vivo by
exploring its ability to lower mean arterial pressure (MAP) in normo-
tensive Sprague-Dawley rats (Fig. 4). When dosed orally in water at 1,
10, and 30 mg/kg, CYR715 reduced MAP in a dose-related manner,
consistent with sGC stimulator pharmacology. At the dose of 30 mg/kg,
CYR715 lowered MAP by 25 mm Hg compared to vehicle.
Fig. 3. Activity of CYR715 on purified human sGC enzyme alone (without NO),
with DETA-NO (30 µM), with DETA-NO (30 µM) and ODQ (10 µM), and with
DETA-NO (30 µM) and Tween-20 (0.2%).
Table 4
Cell potency and in vitro and in vivo PK parameters of IWP-051 and CYR715.
In conclusion, we have described the SAR leading to the discovery of
CYR715, a novel carboxylic acid-containing sGC stimulator. Using key
insights from a pharmacophore model to initiate our effort, we exploited
the C(4) position of the pyrimidine to fine-tune physicochemical prop-
erties. Additionally, metabolic blocking strategies led us to carboxylic
acid-containing analogs, and their migrating acyl glucuronide risk was
addressed. CYR715 has an improved rat pharmacokinetic profile and
demonstrated similar dose-dependent hemodynamic pharmacology in
normotensive rats compared to the previously disclosed IWP-051.10
IWP-051a
CYR715b
Cellular sGC EC50(nM)
97
40
HLM CLint (µL/min/mg)
6
63
MDRI-MDCKII Papp AB (x10-6 cm/s)
Solubility pH 7.0 (µg/mL)
24
40
3
21
t1/2 iv, rat (h)
4.1 ± 0.5
0.6 ± 0.1
25 ± 4.6
96
3.5 ± 1.4
9.2 ± 1.4
3.7 ± 0.7
>100
In vivo rat CL (mL/min/kg)
Oral AUC (h⋅ g/mL)
Oral bioavailability (%)
μ
aIV 0.1 mg/kg, PO 1.0 mg/kg. b IV 1.0 mg/kg, PO 1.0 mg/kg, formulated as the
Declaration of Competing Interest
sodium salt.
All authors are former or current employees of Cyclerion Thera-
peutics and/or Ironwood Pharmaceuticals and may own stock/stock
options.
Acknowledgment
We thank our colleagues at Cyclerion Therapeutics, Inc. especially,
Dr. Vishnu Karnati and Dr. Song Xue for providing starting materials and
intermediates, as well as Dr. Hossein Razavi, Dr. Emily Dertz, and Dr.
Marta Cavero Thomas for helpful discussions.
Appendix A. Supplementary data
Fig. 4. Effects of CYR715 on MAP in normotensive male Sprague-Dawley rats.
Compound CYR715 was formulated as the sodium salt and dosed orally at 1, 10,
or 30 mg/kg in water.
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bmcl.2021.127886.
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