Discovery and SAR studies of 2-alkyl-3-phenyl-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepines as 5-HT7/2 inhibitors leading to the identification of a clinical candidate

Article abstract of DOI:10.1016/j.bmcl.2020.127669

We report here the synthesis and characterization of a dual 5-HT₇ / 5-HT₂ receptor antagonist 3-(4-Fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (4j). 4j is a high affinity 5-HT₇ and 5-HT_2A

Full text of DOI:10.1016/j.bmcl.2020.127669

Journal Pre-proofs
Discovery and SAR Studies of 2-Alkyl-3-phenyl-2,4,5,6,7,8-hexahydropyra‐
zolo[3,4-d]azepines as 5-HT7/2 Inhibitors Leading to the Identification of a
Clinical Candidate
Curt A. Dvorak, Dale A. Rudolph, Diane Nepomuceno, Lisa Dvorak, Brian
Lord, Ian Fraser, Pascal Bonaventure, Timothy Lovenberg, Nicholas I.
Carruthers
PII:
S0960-894X(20)30780-0
DOI:
Reference:
https://doi.org/10.1016/j.bmcl.2020.127669
BMCL 127669
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
10 September 2020
27 October 2020
30 October 2020
Please cite this article as: Dvorak, C.A., Rudolph, D.A., Nepomuceno, D., Dvorak, L., Lord, B., Fraser, I.,
Bonaventure, P., Lovenberg, T., Carruthers, N.I., Discovery and SAR Studies of 2-Alkyl-3-phenyl-2,4,5,6,7,8-
hexahydropyrazolo[3,4-d]azepines as 5-HT7/2 Inhibitors Leading to the Identification of a Clinical Candidate,
Bioorganic & Medicinal Chemistry Letters (2020), doi: https://doi.org/10.1016/j.bmcl.2020.127669
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Discovery and SAR Studies of 2-Alkyl-3-phenyl-
2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepines as
5-HT7/2 Inhibitors Leading to the Identification of a
Clinical Candidate
Curt A. Dvorak,*,a Dale A. Rudolpha, Diane Nepomucenoa, Lisa Dvorakb, Brian Lorda, Ian Frasera,
Pascal Bonaventurea, Timothy Lovenberga, and Nicholas I. Carruthersa
aJanssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121
bEscient Pharmaceuticals, 10578 Science Center Dr, Ste 250, San Diego, CA 92121
ABSTRACT
We report here the synthesis and characterization of a dual 5-HT7 5-HT2 receptor antagonist 3-(4-Fluoro-
phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (4j). 4j is a high affinity 5-HT7 and 5-HT2A
receptor ligand having a pKi = 8.1 at both receptors. It behaves as an antagonist in an in vitro functional
assay for 5-HT2A and as an inverse agonist in an in vitro functional assay for 5-HT7. In a validated in vivo
model for central 5-HT7 activity in rats, blockade of 5-Carboxamidotryptamine (5-CT) induced
hypothermia, 4j shows efficacy at low doses (ED50 = 0.05 mg/kg, p.o., 1 h) and maximal efficacy was
observed at 0.3 mg/kg p.o. with a corresponding plasma concentration of ~ 27 ng/ml. In a validated in
vivo model for central 5-HT2A activity, blockade of 2,5-dimethoxy-4-iodoamphetamine (DOI) induced

head-twitches in mice, 4j shows efficacy at low doses with an ED50 = 0.3 mg/kg p.o. Ex vivo receptor
binding studies demonstrate that 4j occupied 5-HT2A receptor binding sites in the frontal cortex of the
rat brain with an ED50 in good agreement with the ED50 value for central functional effect mediated by
5-HT2A receptor (ED50 = 0.8 mg/kg, p.o., 1h).
-----------------------
In the almost 70 years since serotonin was first isolated and identified as 5-hydroxytryptamine
(5-HT), studies have shown that the biogenic monoamine elicits a complex array of pharmacological and
physiological responses by modulating the activity of numerous 5-HT receptors. This key
neurotransmitter is produced from the amino acid tryptophan and is found in both the peripheral and
central nervous systems. Molecular cloning has confirmed the existence of 14 subtypes of 5-HT
receptors, each encoded by distinct genes.1 Each individual 5-HT receptor subtype can regulate a broad
array of mammalian signaling that can be affected by several variables such as cell type, receptor
number, numbers and types of G-proteins expressed in the target cells, and the specific agonist through
which the receptor is activated. The 5-HT receptors have been divided into 7 subfamilies, by overlapping
pharmacological properties, amino acid sequences, gene organization, and second messenger coupling
pathways. The 5-HT1, 5-HT2, 5-HT4, 5-HT5, 5-HT6, and 5-HT7 receptors couple to G-proteins, whereas the
5-HT3 receptors are ligand gated ion channels.2
The serotonin receptors serve to mediate a diverse range of functions including sleep,
temperature modulation, appetite, learning, mood, and memory. This diversity of function has in turn
fueled an interest in discovery efforts targeting these receptor pathways to improve human health. The
5-HT1 family of receptors are implicated as potential targets for anti-migraine therapy as well as
enhancing the action of serotonin-selective reuptake inhibitors (SSRI’s). Atypical antipsychotic and
2

hallucinogenic drugs have high affinity for the 5-HT2 receptors while the 5-HT3 family are the targets for
antiemetic treatments, which are commonly used in conjunction with chemotherapy. In addition,
numerous approved clinical antipsychotic and antidepressant therapies have high affinities for the 5-
HT6 and 5-HT7 receptors. Indeed, both the 5-HT6 and 5-HT7 receptor types may hold opportunities for
newer and more selective treatments for diseases with fewer of the tolerance issues observed with less
selective therapies which lead to patient non-compliance found with some of the pioneering
medications.3 The 5-HT7 receptor represents the most recently discovered member of the serotonin
family. Protein expression for 5-HT7 can be found in the cortex, thalamus, hypothalamus, septum and
striatum. These receptors are implicated in the mechanism of action of certain antidepressant drugs as
well as regulation of circadian rhythms.
Figure 1. Reported 5-HT7 and 5-HT2A antagonists
Several research groups have been interested in exploring selective 5-HT7 ligands for the
treatment of depression, cognitive dysfunction and sleep disorders. Figure 1 contains the structures of
two reported 5-HT7 antagonists, SB-269970 and JNJ-18038683. SB-269970 represents one of the first
identified potent and selective 5-HT7 antagonists.4 Unfortunately the pharmacokinetic profile of SB-
269970 was not ideally suited for clinical investigation as the compound exhibits high clearance possibly
due to the presence of the phenol moiety. The Neuroscience team at Janssen Research and
Development LLC has also had an interest in 5-HT ligands for the treatment of mood disorders. A high
throughput screening campaign of the Janssen compound collection followed by lead optimization
3

resulted in the identification of the clinical candidate JNJ-18038683, a selective 5-HT7 modulator.
Bonaventure5 et al. has reported on the clinical evaluation of JNJ-18038683 in healthy volunteers and
the compound demonstrated 5-HT7 blockade as measured by changes in sleep parameters, which were
utilized as a surrogate biomarker for target engagement. However, further clinical studies are still
needed to evaluate the full potential of 5-HT7 ligands including JNJ-18038683.
With a clinical candidate in hand a search for a back-up was initiated and this afforded a series
of structures with affinity for multiple 5-HT sub-types. The chemistry evolved to afford a series of
compounds with high affinity for both 5-HT7 and 5-HT2 receptors, most particularly the 5-HT2A subtype.
This additional pharmacological component was perceived as potentially desirable since 5-HT2
antagonism contributes to the efficacy of several antipsychotics and antidepressants. The 5-HT2A
receptor also appears to be the site of action of hallucinogenic compounds (LSD and mescaline are 5-
HT2A agonists), and various antipsychotic and antidepressant drugs display high affinity antagonistic
action on these receptors. Predominant 5-HT2A antagonism is believed to contribute to the easing of
negative symptoms of schizophrenia. Although a host of compounds have 5-HT2A receptor binding as
part of their pharmacological profile, few selective agents have been reported to date (examples include
MDL-100907, ketanserin, and pimavanserin in Figure 1). More recently, pimavanserin (Nuplazid®) was
approved by the FDA for the treatment of psychosis that is associated with Parkinson’s disease. It is also
noteworthy that several selective 5-HT2A PET ligands are available and can be used to study in vivo
receptor occupancy and therefore assist in dose finding studies in humans. Therefore, we envisioned
that a combination of 5-HT7 / 5-HT2A activity would have a desirable pharmacological profile to examine
for the treatment of mood disorders. This current report describes a new series of molecules the team
identified during the discovery efforts on the back-up program for JNJ-18038683 leading to the
identification of a clinical candidate with a dual 5-HT7/5-HT2A antagonist profile.
4

The chemistry used to prepare 2-alkyl-3-phenyl-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepines is
outlined generally in Scheme 1. The sequence utilized -keto ester 1 as a key building block in the
condensation with substituted hydrazines. The reaction appears quite general and both aryl and alkyl
hydrazines added smoothly to provide the regio-isomer 2 as depicted. The addition of a tertiary amine
base, like triethylamine, in the condensation reaction was found to give cleaner reaction profiles in polar
protic solvents such as EtOH, or t-BuOH, leading to improved yields of fused pyrazole 2. Omitting an
amine base or the use of other additives like AcOH or water resulted in the loss of the Boc protecting
group and/or competing ester hydrolysis followed by decarboxylation. The hydroxy pyrazole products
could be isolated but were typically converted directly into less polar triflates with N-phenyltriflamide
for ease of isolation on silica gel chromatography. The Suzuki-Miyaura coupling reaction between
pyrazole triflates and various boronic acid derivatives was carried out using the conditions we have
described previously.6 This resulted in an efficient route to fused azepine pyrazoles with regiocontrol of
the substituents around the pyrazole heterocycle. The three step condensation/coupling/deprotection
sequence allowed for the quick transformation of 1 into a set of fused azepine pyrazoles 4 and a SAR
study was undertaken to determine what effects different N-substituents might have on 5-HT affinity
and additionally what influence aryl substitutions may have on activity profiles and drug-like properties
of the compounds.
From our early work centered around JNJ-18038683, the result of using a non-selective alkylation
on the pyrazole nitrogen to build SAR, it was determined substitutions on the pyrazole had an impact
on 5-HT7 activity. A shift of substitution from N1 to N2 on the pyrazole generally resulted in a reduction
of 5-HT7 affinity, and conversely, an increase in 5-HT2A potency (Table 1). Table 1 contains the structure
activity relationships (SAR) resulting from exploring different small to medium sized groups located on
the pyrazole N2 nitrogen (R1) to establish a more balanced 5-HT7/5-HT2A antagonist profile. In this set
of examples, the activities at both 5-HT7 and 5-HT2A were assessed along with the alpha-adrenergic
5

receptor potency and calculated logP (clogP). Affinity at 5-HT2B and 5-HT2C are also provided for
thoroughness although no attempts were made to address the 5-HT2 subtype selectivity since central 5-
HT2B, 5-HT2C blockade are not believed to be responsible for any undesirable side effects in vivo7.
However, alpha-adrenergic antagonists inhibit smooth muscle contractions which can produce
unwanted changes in blood pressure and thus it was viewed as a potential liability. In addition, a higher
clogP (>4) is a molecular trait that can be associated with lower aqueous solubility, poor metabolic
stability, potential increases in P450 enzyme inhibition, and generally less desirable ADME properties
overall of the compounds.
Scheme 1. General Synthesis of 4a through 4r.
Table 1. SAR studies of 2-alkyl-3-phenyl-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepines.
r5-HT7
h5-HT2A
h5-HT2B
Ki (nM)a
h5-HT2C Ki
(nM)a
r1 Ki
Cmpd
R1
R2
clogP
--
Ki (nM)a Ki (nM)a
(nM)a
18038683
6
100
60
--
--
--
4a
4b
CH3CH2-
H
H
140
75
1200
-
2.29
28
24
19
130
530
2.6
6

4c
H
30
19
43
85
-
2.99
4d
4e
H
H
20
90
30
3
20
3
30
90
600
500
2.34
2.67
4f
4g
4h
4i
H
150
6
600
1
15
2
9000
12
10000
3.7
4-CH3
4-OCH3
4-Cl
4
-
3.09
2.58
3.34
2.77
3.05
2.11
3.54
3.69
3.95
18
3
1
45
9
1
1
18
20
170
16
240
130
-
4j
4-F
8
8
19
24
12
5
49
4k
4l
4-F
(NMe)
40
3
210
390
80
4-CN
4-CF3
90
5
4m
4n
4o
15
2
4-OCF3
3,4-diCl
5000
4000
40
39
20
31
990
910
-
7

4p
2,4-diCl
400
15
43
220
-
3.82
4q
4r
4-F
4-F
100
150
6
1
20
4
200
45
-
2.52
2.85
220
aThe affinity of the compounds for the rat 5-HT7 receptor and human 5-HT2A-c receptors were evaluated by competitive
radioligand binding assay using [3H]5-CT and [3H] ketanserin as radioligands respectively, as described in Bonaventure et al.,
2012.5 Affinity for the rat adrenergic receptor 1 receptor was evaluated in homogenates from rat cortex membranes as
previously described.8 Experiments were performed in duplicate.
A simple unsubstituted aryl ring (R2=H, i.e., phenyl) was appended to C3 of the heterocyclic ring
for compounds 4a through 4f. In examples 4a through 4c, Et, i-Pr, and t-Bu the 5-HT2A activity improves
with each successive methyl group addition and the 5-HT7 potency significantly improves (4a vs 4b) then
plateaus. The 5-HT7 potency then decreases with increasing ring size in examples 4d through 4f. From
this initial set of compounds, it was determined that the isopropyl group provided the best overall
combination of 5-HT7 and 5-HT2A activity along with a clogP under 3 therefore isopropyl was then used
to explore aryl ring substitutions (vide infra). Compounds 4g to 4m detail a select set of substitutions
on the aryl ring (R2). Methyl, chloro, and fluoro groups are all tolerated in the 4 position of the pendant
aryl ring providing excellent potency at both 5-HT7 and 5-HT2A. The addition of a second chlorine atom
to 4i in entries 4o and 4p was not tolerated and a reduction in 5-HT7 potency was observed. The more
polar nitrile group in 4l resulted in a loss of 5-HT7 potency as smaller lipophilic substituents, typically
containing at least one heavy atom, are preferred. Based on this screen the 4-F aryl in 4j had the most
desirable 5-HT7 and 5-HT2A potency and best ratio over the alpha-adrenergic receptor (vs 4g and 4i) in
combination with the lowest clogP. Substituting the basic nitrogen on the azepine with a methyl group
was detrimental for both 5-HT7 activity and the alpha-adrenergic receptor selectivity (4k vs 4j). The
small alkyl rings were then re-examined with the 4-F aryl substituent. Interestingly, the cyclopropyl
8

analogue 4q had increased 5-HT2A and lower 5-HT7 potency (vs 4d). Both exhibited excellent 5-HT2A
potency and reduced 5-HT7 activity suggesting a more selective 5-HT2A profile could also be attained.
On the basis of the dual 5-HT7 and 5-HT2A profile along with a 20 fold window over the in vitro
alpha-adrenergic vs 5-HT potency, a more detailed evaluation of compound 4j was carried out.
Compound 4j behaves as an antagonist at 5-HT2A with a pKB = 8.1 based on an in vitro functional assay
using calcium mobilization. It was also determined to be an inverse agonist at 5-HT7 in a functional assay
for 5-HT7 (cAMP, pIC50 = 7.0). Compound 4j was found to have desirable in vitro ADME properties that
would allow for in vivo evaluation. Binding to plasma proteins was found to be low to moderate with
unbound fractions determined to be 30%fu and 20%fu in human and rat plasma respectively. Metabolic
stability was high in both rat and human liver microsomes (t1/2 > 60 min). No inhibition of cytochrome
P450 enzymes were found up to concentrations of 10 M suggesting that the potential liability for any
drug-drug interactions are minimal. Compound 4j is highly permeable with no efflux potential as
determined by Caco-2 Permeability Assay having an efflux ratio of only 1.3 (Papp A>B 19.5, Papp B>A 25.3
cm/s). Taken together, these ADME properties established the compound to be very well suited for in
vivo profiling.
Indeed, compound 4j was progressed further and was found to be highly orally bioavailable in all
species tested: rat (100%), mouse, dog, (98 %), monkey (72 %) and good exposures were observed in
humans (healthy male volunteers). Acceptable duration of action could be demonstrated after single
oral administration in the dog (p.o. 10 mg/kg, Cmax ~ 2000 ng/ml, t1/2 = 10.6 h and tmax = 30 min) and
non-human primate (p.o. 5 mg/kg, Cmax ~ 300 ng/ml, t1/2 = 11.4 h and tmax = 3 h). These data for
exposures rats are shown in Table 2. An experiment designed to establish CNS penetration after an oral
dose in rats determined that the brain to plasma ratio for 4j was >1.
Table 2. Pharmacokinetics and BBB of 4j in rats
9

dose
tmax (h)
Cmax
AUC
Clearance
L/h
t (h)
½
umol/L h*umol/L
(ng/ml)
i.v. 1 mg/kg
p.o. 3 mg/kg
2.8
0.4
0.4
3.4
4.3
1.7
0.7
(190)
9.2
7.7
s.c. 3 mg/kg
0.75
0.94
0.4
3.9
(260)
p.o. 10 mg/kg
Plasma
1
1
3.9
(1076)
57
89
0.2
0.1
6.0
6.3
Brain
6.1
(1680)
Given the favorable in vitro and ADME profile of 4j the compound was progressed further into
the project flowchart and into the in vivo models used to establish both 5-HT7 and 5-HT2A target
engagement. The 5-HT7 in vivo screen was performed using rats implanted with a telemetry device
capable of measuring various data streams including body temperature. In the 5-HT hypothermia
model, rats are dosed with 5-Carboxamidotryptamine (5-CT) which results in a reduction of body
temperature and this effect can be blocked by a 5-HT7 antagonist. In addition, 5-CT does not produce
hypothermia in 5-HT7 knockout animals confirming that the effect is due to central 5-HT7 antagonism.9
In this model, compound 4j shows efficacy at very low doses with an established of ED50 = 0.05 mg/kg
for the blockade of induced by 5-CT hypothermia. The maximal efficacy was observed at 0.3 mg/kg p.o.
corresponding to a plasma concentration of ~27 ng/ml which was used to support an estimate of the
10

exposures required in human, and for human dose predictions. Compound 4j by itself had no effect on
body temperature at these doses. The established in vivo model for 5-HT2A target engagement is the
blockade of 2,5-dimethoxy-4-iodoamphetamine (DOI) induced head-twitches in mice.10 Indeed, in the
DOI induced head-twitch model compound 4j shows efficacy at low doses with an established ED50 = 0.3
mg/kg p.o. (Figure 2 B). Ex vivo receptor occupancy was also examined with compound 4j. This ex vivo
binding study demonstrates that compound 4j occupied 5-HT2A receptor binding sites found in the
frontal cortex area of rat brain with an ED50 in good agreement with the ED50 value for central functional
effect mediated by 5-HT2A receptor (ED50 = 0.8 mg/kg, p.o., 1h) (Figure 2 C). In addition, in an in vivo
model for adrenergic alpha-1 activity, 4j shows only weak activity in the blockade of phenylephrine
induced mydriasis5 in rat corresponding to a plasma exposure 30-fold above the minimum effective dose
established in the 5-CT hypothermia model.
In a broader selectivity profile of compound 4j, greater than 50-fold selectivity over the primary
activity was found vs a panel of 50 monoamine and peptide hormone receptors, ion channels and
neurotransmitter uptake sites (with the exception of the 5HT receptors contained therein). The 5-HT2
receptors do display high sequence homology and compound 4j also shows in vitro affinity for the h5-
HT2B and 5-HT2C receptors with pKi 7.6 and 7.3, respectively. Compound 4j behaves as an antagonist on
both 5-HT2B and 5-HT2C.
Figure 2: A) Body temperature trace of Compound 4j dose-response to 5-CT induced hypothermia in rats. A: given p.o. 20
min prior to 5-CT (0.1 mg/kg i.p.) administration (n = 4). The arrows indicate administration time. B) Antagonism of DOI-
induced head-twitches by Compound 4j after s.c. (20 min) or oral (60 min) administration. Data are expressed as percent
inhibition vs vehicle treated group (n = 4). C) Ex vivo 5-HT2A receptor occupancy with Compound 4j in rat frontal cortex: dose-
dependency after oral administration (t = 60 min, n = 3).
11

A
39
38
37
36
35
34
Vehicle p.o.
0.03 mg/kg p.o.
0.1 mg/kg p.o.
0.3 mg/kg p.o.
1 mg/kg p.o.
Compound
4j
5-CT
0
50 100 150 200 250 300 350 400
Time (min)
B
120
100
80
60
40
20
0
p.o.
s.c.
0.001
0.01
0.1
1
10
Dose Compound 4j (mg/kg)
C
12

120
110
100
90
80
70
60
50
40
30
20
10
0
-10
0.01
0.1
1
10
Dose Compound 4j mg/kg (p.o.)
The synthesis and SAR studies of a series of 2-alkyl-3-phenyl-2,4,5,6,7,8-hexahydropyrazolo[3,4-
d]azepines has been described. The SAR exploration was undertaken to examine the 5-HT activity of a
set of small to medium groups appended to the N2 pyrazole nitrogen. It was determined that an
isopropyl group offered optimal activity at 5-HT7 / 5-HT2A with the best selectivity achieved over the
alpha-1 adrenergic receptor. Small lipophilic substituents were tolerated on the aryl ring at C3 of the
pyrazole and compound 4j was identified as a dual 5-HT7 / 5-HT2A antagonist. Compound 4j had
acceptable ADME properties and good oral bioavailability in all species tested. In the in vivo animal
models used to assess target engagement, in the blockade of 5-CT induced hypothermia for central 5-
HT7 activity in rats, 4j shows efficacy at low doses with an ED50 = 0.05 mg/kg (p.o., 1 h) and maximal
efficacy was observed at 0.3 mg/kg p.o. corresponding to a plasma concentration of ~27 ng/ml. In an in
vivo model for central 5-HT2A, blockade of DOI-induced head-twitches in mouse, 4j also shows efficacy
at low doses with an ED50 = 0.3 mg/kg p.o. Safety and tolerability trials were undertaken with compound
4j, (JNJ-26528398) and was subsequently selected as a clinical candidate. An alternative pyrazole ring
construction was developed for the scale-up GMP synthesis efforts of JNJ-26528398.11
13

Acknowledgments. The authors are grateful to Discovery Sciences for DMPK and bioanalysis. We
would also thank Professor Dale Boger for useful discussions regarding the condensation of hydrazines
and -keto esters.
References and Notes.
Graphical abstract
1
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