Expert Opinion on Therapeutic Patents

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Recent discovery and development of non-peptide

vasopressin V2 receptor agonists

Kazumi Kondo

To cite this article: Kazumi Kondo (2002) Recent discovery and development of non-peptide
vasopressin V2 receptor agonists, Expert Opinion on Therapeutic Patents, 12:8, 1249-1258, DOI:
10.1517/13543776.12.8.1249

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Published online: 25 Feb 2005.

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 Review

Recent discovery and

development of non-peptide
vasopressin V2 receptor agonists
1. Introduction Kazumi Kondo
Medicinal Chemistry Research Institute, Otsuka Pharmaceutical Co. Ltd, 463-10 Kagasuno Kawauchi-
2. Discussion
cho, Tokushima 771-0192, Japan
3. Reported non-peptide
arginine vasopressin agonists Desmopressin, 1-desamino-8-D-arginine vasopressin (DDAVP), is a peptide ana-
4. Expert opinion logue of arginine vasopressin (AVP), which is an agonist of the AVP V2 receptor.
It is used for the treatment of central diabetes insipidus, the control of noctur-
nal enuresis and may also be of use for controlling nocturia. However, DDAVP is
a peptide analogue with variable bioavailability, even via an intranasal route or
in oral formulation. Therefore, the discovery and the development of an orally
effective non-peptide V2 agonist may be particularly useful in all respects. The
continuous filing of patents since 1995 evidences the importance of this field.

Keywords: agonist, arginine vasopressin (AVP), bioavailability, diabetes insipidus, mimic, modulator,
nocturia, nocturnal enuresis, non-peptide, orally effective, polyuria, receptor, V 2 receptor, vasopressin

Expert Opin. Ther. Patents (2002) 12(8):1249-1258

1. Introduction

The cyclic nona-peptide arginine vasopressin (AVP) is a well-known hormone that

exerts its major actions through three well-defined receptor subtypes: V1a, V1b and V2
[1-6]. The V1a receptor subtype, which exists mainly in vascular smooth muscle cells,
platelets, liver, adrenal glands and uterus, causes contraction and proliferation of vas-
cular smooth muscle, platelet aggregation, coagulation factor (Factor VIII) release and
glycogenolysis. The V1b receptor is associated with the pituitary gland and is involved
in the corticotropic response to stress through regulation of adenocorticotropic hor-
mone (ACTH) secretion and the potentiating effect on corticotropin-releasing hor-
mone (CRH). The V2 receptor is present in the collecting duct of the kidney.
Vasopressin-induced antidiuresis, mediated by renal epithelial V2 receptors, helps to
maintain normal plasma osmolality, blood volume and blood pressure. Many
attempts to develop a peptide V2 receptor antagonist for treating diseases character-
ised by excess renal reabsorption of free water have been reported. Peptide V2 antago-
nists may correct the fluid retention and hyponatraemia observed in congestive heart
failure, liver cirrhosis and nephrotic syndrome. Marked species differences and incon-
sistencies have been revealed between the in vitro and in vivo assay systems as reported
in the case of compound 1 [7-10]. Drug discovery efforts for finding non-peptide V1a
antagonist (2) were first reported in 1991 by Otsuka [11-13]. This compound appeared
as the first orally-active selective non-peptide V1a receptor antagonist. Species differ-
ences in the binding affinity for the V1a receptor between rats and humans were
reported by other research groups [14-18]. Interestingly, compound 2 was reported to
show the same order of magnitude in binding affinity for the oxytocin (OT) receptor
between humans and rats. Additional modifications were reported by Merck as a
selective OT receptor antagonist leading to compound 3, which showed good oral
bioavailability and selectivity for the human OT receptor [19-23]. Non-peptide com-
pound 4 was reported to be an orally-active and selective V2 receptor antagonist
Ashley Publications by Otsuka in 1992 [24-32]. This compound having a diverse structure from that of
[Link] compound 2 showed its aquaretic effect in clinical tests and proved to be an orally-
active V2 receptor antagonist. A third structural class of non-peptide, compound 5,

2002 © Ashley Publications Ltd ISSN 1354-3776 1249

Recent discovery and development of non-peptide vasopressin V2 receptor agonists

Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH2 AVP

S-CH2-CH2-CO-Try-Phe-Gln-Asn-Cys-Pro-D-Arg-Gly-NH2 DDAVP

CH2-CO-D-Tyr(Et)-Phe-Val-Asn-NH-CH-CO-Arg-D-Arg-NH2

C C CH2
H2 H2

N N
O O

N N
O
O O

N O
O
O O N
N
H

2 3 O
N

Cl
O
N HO
Cl
N O
O O
O
O N H
O N H
NH2 N
O O
N S O S
H
O O O
O O

4 5 6
was reported in 1993 as a V1a antagonist by Sanofi [15-17]. This compound from an agonist to an antagonist [59]. Therefore, V2
compound showed very potent affinity for both rat and human agonists might be found during the development of V2 antago-
V1a receptors. The final structural class of non-peptide, com- nists. In this review, non-peptide V2 agonists will be discussed for
pound 6, was disclosed as a V2 antagonist in 1996 by Sanofi [33- each structural class of compounds. Some of those may be antag-
35]. Many analogous derivatives from these four structural onists, for which no biological data were provided in the patent.
classes were disclosed as V1a, V2 and OT antagonists [36-49]. The claimed compounds are classified by the typical structures
The definitive characterisation and the function of AVP and whose activities are shown in the patent. Other claimed com-
OT receptors have become possible since the successive cloning pounds without any activities are not classified in this review. If
studies of the V1a, V1b, V2 and OT receptors [50-56]. These recep- the biological data for a number of agonists are shown in a patent,
tors were confirmed to be a superfamily of the G-protein-coupled those relevant have been extracted by the author in this review.
receptors (GPCRs). Some studies on mutagenesis and molecular
modelling of AVP receptors, to consider species differences 2. Discussion
were reported but no definitive work has yet been published
[57,58]. The non-peptide V2 agonist may be beneficial for the 2.1 Indole analogue
treatment of central diabetes insipidus, urinary incontinence and Sanofi has claimed 1,3-dihydroindol-2-one derivatives substi-
nocturnal enuresis by oral administration. A small difference in tuted at position 3 with a nitrogen group as agonists or antago-
the structure of the receptor ligand can switch the activity of the nists of the vasopressin and/or OT receptors [101]. No concrete

1250 Expert Opin. Ther. Patents (2002) 12(8)

 Kondo

Cl N
Cl
NH2 NH
Cl Cl NH2
Cl
O O
O
N H
N N N
O
O S N
S O
O O N
O O O

7 8

9
O O

N N
N N

Cl Cl

N N
O
O O

10 11
O

biological data were given to specify a compound having agonist affinity (IC50, 0.018 µM) for the human V2 receptor and potent
activity. Compound 7 is an example of a claimed structure. Some agonist activity (79.3% PMA (percentage of the maximal cAMP
further modifications on an amino group at position 3 and a sub- accumulation at a concentration of 10-6 M)). The pyrrolidino-
stituent at position 1 were also included (compounds 8 and 9). derivative, compound 14, also showed potent binding affinity
(IC50, 0.009 µM) and agonist activity (64.5%, PMA). After
2.2 Benzazepine analogue superposing compounds 13 and 14 and considering the SAR on
Otsuka has claimed benzoheterocyclic derivatives to be useful as 3D, compound 15 (IC50, 0.051 µM, PMA, 73.2%) and com-
vasopressin or OT modulators [102]. Biological data to prove ago- pound 16 (IC50, 0.013 µM, PMA, 68.3%) were designed, syn-
nist activity were given for compound 10. The amount of urine thesised and evaluated. These compounds proposed the
excreted 2 h postoral administration at a dose of 1 mg/kg is a sixth optimum structural requirements on a benzazepine scaffold for
of that in the control group using untreated and unstrained Brattle- agonist activity.
boro rats. One structurally similar analogue (compound 11), was
shown to have V1a antagonist activity (ID50 = 2.8 mg/kg, dose 2.2.2 Tricyclic benzazepine analogue (pyrrolo
required to reduce the increase in diastolic pressure caused by the [2,1-c][1,4]benzodiazepine derivatives)
administration of AVP, 30 mU/kg i.v., to 50% of its control value). American Home Products has claimed pyrrolo[2,1-
c][1,4]benzodiazepine derivatives as vasopressin antagonists
2.2.1 Benzazepine analogue [104]. The binding affinities for the V1a and the V2 receptor
Otsuka has also claimed benzazepine derivatives as vasopressin were measured using human platelets and a human V2
agonists shown in formula I [103]. The agonist activity of com- receptor expressed mouse fibroblast cell line, respectively.
pound 12 (419% above basal at a concentration of 10-6 M) Compound 17 showed potent affinity for the V1a receptor
was shown as the increased ratio of the cAMP amount based and moderate affinity for the V2 receptor (IC50, V1a = 0.0029,
on the control group. This is the first example to prove ago- V2 = 0.39 µ M). After administration of compound 17
nist activity using cells prepared by introducing a gene coding (10 mg/kg p.o.) followed by administration of AVP (0.4 µg/
human V2 receptor into HeLa cells. kg in peanut oil i.p.), a reduction in urine volume (3.5 ml, 0
Kondo et al. published the structure–activity relationship – 4 h) and an increase in urine osmolality (1598 mOsm/kg)
(SAR) of benzazepine derivatives as V2 agonists [59]. The pro- were observed in conscious hydrated rats (control,
pylamino-derivative, compound 13, showed potent binding 13.3 ± 0.3 ml; 0 – 4 h, 229 ± 6 mOsm/kg; +DMSO(10%),

Expert Opin. Ther. Patents (2002) 12(8) 1251

Recent discovery and development of non-peptide vasopressin V2 receptor agonists

O
O R2
N
N N
R1
A R3

N
N Cl
O
O
R4

R5 N

Formula I 12

N Cl N Cl N Cl
N Cl

O O O
O
N
N N N
N
H
13 14 15 16

N N

N N

O O

17 18
12.1 ± 1 ml; 0 -– 4 h, 497 ± 53 mOsm/kg; AVP-control, agonist activity (88% decrease in urine volume, 663% increase
2 ± 0.2 ml; 0 – 4 h, 1226 ± 58 mOsm/kg). This increase in urinary osmolality) by oral administration (10 mg/kg).
in urine osmolality should be thought of as the result of V2 [Link] Tricyclic benzazepine analogue (6,11-dihydro-5H-
receptor-mediated reabsorption of water, which is higher pyrido[2,3-b][1,5]benzodiazepine derivatives)
than AVP-control. The antagonistic action would be seen in American Home Products has claimed 6,11-dihydro-5H-
this experiment but the partial agonist action would not be pyrido[2,3-b][1,5]benzodiazepine derivatives as vasopressin
excluded. The binding affinity for the V2 receptor was agonists [106]. The 3-methyl-1H-pyrazole substituted ana-
enhanced by adding a n-Pr group (18, IC50, V1a = 0.012, V2 logue, compound 22, showed very potent agonist activity
= 0.058 µM), the in vivo activity was similar (4. 5ml, 0-4 h, (98% decrease in urine volume, 1363% increase in urinary
1347 mOsm/kg, 10 mg/kg, po) to that of compound 17. osmolality, 4 h) by oral administration (1 mg/kg) in normal
[Link] Tricyclic benzazepine analogue (pyrrolo[2,1-c] conscious water-loaded rats. The 5-methyl-1H-1,2,4-triazole
[1,4]benzodiazepine derivatives) substituted derivative, compound 23, was also found to be a
American Home Products has claimed pyrrolo[2,1-c][1,4]ben- potent agonist (86% decrease in urine volume, 615% increase
zodiazepine derivatives as vasopressin agonists [105]. 3-Methyl- in urinary osmolality, 10 mg/kg, p.o.).
1H-pyrazole derivative, compound 19, reduced urine volume [Link] Tricyclic benzazepine analogue (6,11-dihydro-5H-
(80% decrease versus control) and increased urinary osmolality pyrido[2,3-b][1,5]benzodiazepine 1-oxide derivatives)
(306% change as per cent of control) in normal conscious American Home Products has claimed 6,11-dihydro-5H-
water-loaded rats by oral administration (1 mg/kg). Pyrimidine pyrido[2,3-b][1,5]benzodiazepine 1-oxide derivatives as vaso-
derivative, compound 20, was proved to be a weak agonist pressin agonists [107]. The pyridine N-oxide 24 also showed
(25% decrease in urine volume, 152% increase in urinary potent agonist activity (80% decrease in urine volume, 753%
osmolality, 4 h) by oral administration (1 mg/kg). 4-Ethynyl- increase in urinary osmolality, 10 mg/kg, p.o., 4 h) using nor-
substituted analogue, compound 21 appeared to show potent mal conscious water-loaded rats.

1252 Expert Opin. Ther. Patents (2002) 12(8)

 Kondo

N N N

F F
N F N F N Cl
F F
O O N O
N N
N N N

19 20 21

N N O
H +
H N N
N H
N
F
F N
N Cl
F N Cl
O
O
O
N N
N N
N
N N
H
22 23 24

N
H
N N N S

N
N Cl N Cl N

O O
O O O
S S N
Cl N H
Cl
Cl

25 26 27 28
2.2.3 Tricyclic
benzazepine analogue having shown but the strength of activity was weak compared with
thienylbenzoyl moiety that of compound 27.
American Home Products has claimed tricyclic analogues
having a thienylbenzoyl substituent on the scaffold [108]. The 2.3 Bicyclic benzazepine analogue (5,6,7,8-tetrahydro-
5-chloro derivative, compound 25 was shown to be a potent 4H-thieno[3,2-b]azepine derivatives)
agonist (74% decrease in urine volume, 819% increase in uri- American Cyanamid has claimed 5,6,7,8-tetrahydro-4H-
nary osmolality, 10 mg/kg, p.o., 4 h) using normal conscious thieno[3,2-b]azepine derivatives as vasopressin antagonists [110].
water-loaded rats. The pyridobenzodiazepine derivative, com- The binding affinities for both V1a and V2 receptors were
pound 26, reduced the urine volume (74%, 10 mg/kg, p.o., 4 h) shown using rat liver plasma membranes and rat kidney medul-
but the change in urinary osmolality was moderate (365%) lary membranes, respectively. Compound 28 showed potent
compared with 25. binding affinity for both V1a and V2 receptors (IC50,
V1a = 0.0037, V2 = 0.0026 µM). A small amount of urine
2.2.4 Tricyclic benzazepine analogue having indole (2.8 ml) was collected for 4 h after oral administration of com-
moiety pound 28 (10 mg/kg) to conscious hydrated rats. This result
American Home Products has claimed tricyclic analogues hav- does not explain whether the activity is agonist or antagonist.
ing an indole substituent on the scaffold [109]. 1-Methyl-1H- AVP was administered intraperitoneally to each rat following
indole derivative, compound 27, showed agonist activity 1 h of oral administration of a test compound. No data were
(66% decrease in urine volume, 174% increase in urinary shown for the control in this experiment. Considering the high
osmolality, 10 mg/kg, p.o., 4 h) using normal conscious binding affinity for the V2 receptor and the small urine volume
water-loaded Sprague-Dawley rats. The agonist activity for obtained, these results can be explained by antagonistic activity,
some other benzohetero-ring-substituted analogues was partial agonist activity or by its poor oral bioavailability.

Expert Opin. Ther. Patents (2002) 12(8) 1253

Recent discovery and development of non-peptide vasopressin V2 receptor agonists

N
H S

N N
O
S
O O
N Cl H H
N N N N

O
O N Cl O N
O O
N
29 30 31

S
O
N

N
N O
O
O
O H
H N N
N N

Cl O N
O N S
S
32 33

N N

O O O
O
H H H
H N N
N N N
O

O O
34 35

2.3.1Bicyclic benzazepine analogue (5,6,7,8- not be understood by its intrinsic activity and/or by its bio-
tetrahydro-4H-thieno[3,2-b]azepine derivatives) availability.
Otsuka published 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine
derivatives as vasopressin agonists [111]. The agonist activity of 2.4.1 Benzazepine analogue with urea moiety
the pyrrolidine-substituted analogue, compound 29 was Ferring has claimed benzazepine analogues as vasopressin
shown by the increased percentage of cAMP (366% of con- agonists [113]. The agonist activity was shown as the per
trol, 10-6 M) using human V2 receptor-expressed HeLa cells. cent of inhibition of urine output using Brattleboro rats
by oral administration of the compounds (1 mg/kg). The
2.4 Bicyclicor tricyclic azepine analogue with ester, compound 34, showed potent agonist activity (74%
pyrrolidine-2-carboxamide substituent inhibition), as did the amide, compound 35 (58%). Some
Ferring has claimed benzazepine derivatives having pyrroli- biological data for the claimed compounds were shown in
dine-2-carboxamide as vasopressin agonists [112]. The ago- this patent.
nist action was shown as the per cent inhibition of urine
output for 1 h using Brattleboro rats. Potent agonist activi- 2.4.2 Benzazepine analogue with urea moiety (N-
ties were seen following oral administration (1 mg/kg) of phenylurea)
compound 30 (82%), thienoazepine derivative compound Ferring has claimed benzazepine analogues as vasopressin ago-
31 (90%), pyrrolo[1,2-a][1,5]benzodiazepine derivative nists [114]. Agonist activity was reported as an EC50 value, being
compound 32 (81%) and thieno[3,4-b][1,5]benzoxazepine that concentration of compound necessary to cause a half-max-
derivative compound 33 (88%). The agonist activities for imal cellular activation. 2,6-Difluoroaniline-substituted ana-
some tricyclic azepine derivatives were also given in this logues (36 – 38) showed potent activity (EC50, 4 nM, 16 nM,
patent. The binding affinity for each compound was not 10 nM, respectively). No precise conditions and reference for
shown; therefore, the strength of the agonist activity could this in in vitro experiments were shown in this patent.

1254 Expert Opin. Ther. Patents (2002) 12(8)

 Kondo

N
S

N N N

O F O O F
F
H H H H H H
N N N N N N

O O O
F F F
36 37 38

O
N
H
HO
N

N Cl N Cl N

O O O O
N
N N
N
H

39 40 41

3. Reported non-peptide AVP agonists with compound 39, significant and constant antidiuresis was
observed. In male Sprague-Dawley rats with normal plasma
AVP levels, compound 39 at 0.03 – 3 mg/kg also produced
3.1 (R)-2-[1-(2-Chloro-4-pyrrolidin-1-yl-benzoyl)-2,3,4,5- dose-dependent antidiuretic action (urine volume from
tetrahydro-1H-1-benzazepin-5-yl]-N-isopropylacetamide 2.6 ± 0.6 to 1.1 ± 0.2 ml at 0 – 4 h postdosing). This com-
(OPC-51803) pound did not change blood pressure or heart rate or inhibit
Nakamura et al. reported on the characterisation of com- AVP-induced pressor response even at 30 mg/kg p.o.
pound 39 (OPC-51803) in cells expressing human vasopressin
receptor subtypes [59]. Compound 39 displaced [3H]-AVP 3.2 [2-Chloro-4-(3-methyl-pyrrazol-1-yl)-phenyl]-(5H,
binding to human V 2 and V1a receptors with Ki values of 11H)-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-
91.9 ± 10.8 nM (n = 6) and 819 ± 39 nM (n = 6), respec- methanone (VNA-932)
tively. Agonist action for the V2 receptor was demonstrated as Chan et al. reported compound 40 (VNA-932) to be a non-
increasing cAMP production in HeLa cells expressing human peptide of an orally-active and selective V2 receptor agonist
V2 receptors with an EC50 value of 189 ± 14 nM (n = 6). This [49,62-64]. This compound inhibited [3H]-AVP binding to cloned
compound did not increase the intracellular Ca2+ concentra- human AVP V2 and V1a receptors expressed in LV2 cells with K i
tion ([Ca2+]i) in HeLa cells expressing the human V1a recep- values of 40 ± 1 and 465 ± 16 nM, respectively. In the same cells
tor. Based on these results, this compound has been expressing human V2 receptors, compound 40 stimulated the
confirmed to be the first non-peptide agonist for the human formation of cAMP in a concentration-dependent manner with
AVP V2 receptor without agonist activity for the V 1a receptor. EC50 = 0.73 ± 0.1 nM. This compound decreased urine volume
The antidiuretic effects of this compound were also reported and increased urinary osmolality in a dose-dependent manner
by Nakamura et al. following oral administration to rats [60]. with oral ED50 values of 0.2 ± 0.23 (rat), 0.1 ± 0.01 (Brattleboro
At single oral doses of 0.003 – 0.3 mg/kg in female Brattle- rat), 0.1 ± 0.04 (dog) and 0.28 ± 0.0 5mg/kg (monkey), respec-
boro rats, compound 39 decreased urine volume (from tively. In a 5- day daily dosing study in rats, compound 40 did
10.8 ± 1.1 to 0.5 ± 0.2 ml during 2 h postdosing) and increased not produce tolerance. This compound (30 mg/kg, p.o.) also
urinary osmolality (from 114 ± 9 to 432 ± 114 mOsm/kg) in a did not produce haemodynamic effects over 4 days of continu-
dose-dependent manner. During the period of 4-week treatment ous monitoring in conscious rats.

Expert Opin. Ther. Patents (2002) 12(8) 1255

Recent discovery and development of non-peptide vasopressin V2 receptor agonists

4. Expert opinion 41 was proved by clinical studies. This is the first study to
predict the antagonistic action for the human V2 receptor.
In the last decade, there has been remarkable progress in the The prediction of agonist activity for the human V2 receptor
development of non-peptide compounds, selective and will also be expected by monitoring cAMP production.
orally bioavailable antagonists of AVP receptors [45-49]. Dur- Since the discrepancy in binding affinity between rats and
ing the research efforts for such antagonists, some com- humans for the V2 receptor was reported for several com-
pounds have been found to be agonists for the V2 receptor. pounds [59], the difficulty of evaluating efficacy by oral
No compound with agonist activity for V1a, V1b or OT administration in humans still remains when using animal
receptors has been reported. The definitive prediction of the models due to the differences in bioavailability, binding
species differences in binding affinity and of agonist or affinity and agonist activity between human and animal
antagonist activity will be performed using human receptor- models. The non-peptide compounds, OPC-51803 and
expressed cells. Yamamura et al. reported the antagonistic VNA-932, were reported as orally effective agonists and the
activity of compound 41 (OPC-41061) for the human V2 agonist activities were proven using human receptor
receptor by examining the effect of this compound on ade- expressed cells. Efficacy in humans will be proven by clinical
nylyl cyclase activity using human V2 receptor-expressed studies, which will be expected to be useful for treating dis-
HeLa cells [30]. Further, the antagonist action of compound eases of low AVP levels by oral administration.

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53. SUGIMOTO T, SAITO M, 62. CHAN PS, PARK CH, LAI FM et al.: Affiliation
MOCHIZUKI S, WATANABE Y, VNA-932, a non-peptide orally-active and Kazumi Kondo PhD
HASHIMOTO S, KAWASHIMA H: selective vasopressin V2 receptor agonist, Medicinal Chemistry Research Institute, Otsuka
Pharmaceutical Co. Ltd, 463-10 Kagasuno
Molecular cloning and functional produces potent antidiuretic effects in
Kawauchi-cho, Tokushima 771-0192, Japan
expression of cDNA encoding the human conscious rats, dogs and monkeys. World
Tel: +81 88 665 2126; Fax: +81 88 665 6031;
E-mail: k_kondo@[Link]

1258 Expert Opin. Ther. Patents (2002) 12(8)