Synthesis, SAR and selectivity of 2-acyl- and 2-cyano-1-hetarylalkyl- guanidines at the four histamine receptor subtypes: A bioisosteric approach

Article abstract of DOI:10.1039/c3md00245d

In the search for potential bioisosteres of the 4-imidazolyl ring in acylguanidines (e.g. UR-AK24), known to possess affinity to several histamine receptor subtypes (H_xR, x = 1-4), and cyanoguanidine-type H ₄R agonists (e.g. UR-PI376

Full text of DOI:10.1039/c3md00245d

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Synthesis, SAR and selectivity of 2-acyl- and
2-cyano-1-hetarylalkyl-guanidines at the four
histamine receptor subtypes: a bioisosteric
approach†
Cite this: Med. Chem. Commun., 2014,
5, 72
*
Roland Geyer,‡ Patrick Igel,‡ Melanie Kaske, Sigurd Elz and Armin Buschauer
In the search for potential bioisosteres of the 4-imidazolyl ring in acylguanidines (e.g. UR-AK24), known to
possess affinity to several histamine receptor subtypes (HxR, x ¼ 1–4), and cyanoguanidine-type H4R
agonists (e.g. UR-PI376), the contribution of various heterocycles to agonism, antagonism and HR
subtype selectivity was studied (recombinant human H1,2,3,4Rs, isolated guinea pig organs (H1R, H2R)).
While minor structural modifications of UR-PI376 analogues were not tolerated regarding H4R agonism,
in the case of the acylguanidines, a 1,2,4-triazole ring shifted the selectivity toward the H2R.
Received 30th August 2013
Accepted 6th November 2013
DOI: 10.1039/c3md00245d
www.rsc.org/medchemcomm
Guanidine-type compounds like arpromidine and analogues
represent highly potent H2R agonists.25,26 Drawbacks due to the
Introduction
strongly basic guanidine, e.g. very low oral bioavailability and
lack of penetration across the blood brain barrier, were elimi-
nated by replacing the guanidine group with a considerably less
basic acylguanidine moiety (Fig. 1, UR-AK24 (1)).27–29 However,
these NG-acylated imidazolylpropylguanidines developed as
H2R agonists lacked selectivity toward the hH3R and hH4R.30 By
analogy with the H2R agonist amthamine (2),31 the replacement
The physiological and pathophysiological effects of the biogenic
amine histamine are mediated through four receptor subtypes,
referred to as H1, H2, H3 and H4 receptors (H1R, H2R, H3R, and
H4R), all belonging to class A of G protein coupled receptors.1–4
H1R and H2R antagonists have been used for decades in the
treatment of allergic conditions and as antiulcer drugs,
respectively. The H3R is mainly expressed in the brain and is
considered a promising drug target, for instance, for the treat-
ment of attention-decit hyperactivity disorder, Alzheimer’s
disease, Parkinson’s disease, sleep disorders or obesity.5 The
H4R was discovered by several groups based on its high
sequence homology with the H3R.6–12 The expression on
hematopoietic cells such as mast cells, basophils, eosinophils,
T-cells and dendritic cells suggests a role of the H4R in the
regulation of immune responses and inammation.13–15 There-
fore, the H4R is considered a potential drug target for the
treatment of diseases like allergic rhinitis, rheumatoid arthritis,
bronchial asthma and pruritus.16–18 Recent reports on b-
arrestin-mediated signalling19–21 of H4R ligands and partial
agonistic effects of the standard H4R antagonist JNJ-7777120
(ref. 22) at certain H4R species orthologs suggest that the
interpretation of ligand effects in vivo in terms of agonism or
antagonism should be interpreted with caution.19,23 Hence, both
selective antagonists and agonists are required as pharmaco-
logical tools to further explore the role of the H4R.15,24
Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry, Faculty of Chemistry and
¨
Pharmacy, University of Regensburg, Universitatsstr. 31, D-93053 Regensburg,
Fig.
1 Structures of the selective H4R agonists 5-methylhistamine,
VUF8430 and OUP-16, the NG-acylated imidazolylpropylguanidine
UR-AK24 (1), which is active at the H2R, H3R and H4R, the H2R agonist
amthamine (2), related potent and selective acylguanidine-type H2R
agonists 3 and 4 and the potent and selective H4R agonist UR-PI376 (5).
Germany. E-mail: armin.buschauer@ur.de
† Electronic supplementary information (ESI) available: Synthesis procedures,
analytical data and pharmacological methods. See DOI: 10.1039/c3md00245d
‡ These authors contributed equally to this work.
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Fig. 2 Imidazole replacement in acylguanidine-type non-selective H2R agonists and in cyanoguanidine-type H4R agonists. Overview of the
introduced aromatic rings.
of the imidazole ring in acylguanidine-type ligands by a triazolylpropanol 20 was obtained in ve steps starting from
2-amino-thiazole ring, resulted in selective H2R agonists (3 and 1H-1,2,4-triazole (15). Aer trityl-protection of 15,43,44 16 was
4).27,32,33 In contrast potent selective agonists for the hH4R were treated with n-BuLi and DMF in THF to afford the aldehyde 17.45
obtained by replacing the basic acylguanidine group with a cya- Elongation of the side chain by two carbon atoms was carried
noguanidine moiety as in UR-PI376 (5).34 The highest potency out via the Horner–Wadsworth–Emmons reaction employing
resided in imidazolylalkylcyanoguanidines with a tetramethylene triethyl phosphonoacetate.46 Subsequent hydrogenation of the
linker, connecting the imidazole and the cyanoguanidine moiety. C]C double bond and reduction of the ethyl ester yielded 20.
Unlike hH4R agonists such as 5-methylhistamine,35 VUF-8430 Conversion of the pyridylpropanols 21–23 to the corresponding
(ref. 36) or OUP-16 (ref. 37) compound 5 is devoid of agonistic phthalimides 24–26 under Mitsunobu conditions47 followed by
activities at hHR subtypes other than the hH4R.34
hydrazinolysis gave the pyridylpropylamines 27–29.48
The previous results suggest that the bioisosteric approach
The arylpropylguanidines 44–52 were synthesized starting
harbours the potential of further increasing the preference or the from the corresponding arylpropyl alcohols 8, 10, 14 and 20 or
selectivity of hetarylalkylguanidines for a certain HR subtype. In arylpropylamines 27–31 (Scheme 2). Conversion of the alcohol
the present work various heterocycles were introduced to replace to the di-Cbz-protected guanidines 35–38 was accomplished
the 1H-imidazol-4-yl ring (Fig. 2). Special attention was paid to under Mitsunobu conditions47 by analogy with the procedure
substructures known from early studies on hetaryl analogues of described by Feichtinger et al.49 The arylpropylamines 27–31
histamine.38,39 These structural modications were combined were treated with the triyl-di-Cbz-protected guanidine 34 (ref.
with an acylguanidine or a cyanoguanidine moiety as less basic or 49) to give the di-Cbz protected arylpropylguanidines 39–43.
non-basic guanidine replacements.
Finally, the arylpropylguanidines 44–52 were obtained by
hydrogenolytic cleavage of the Cbz groups. The NG-acylated
arylpropylguanidines were prepared as outlined in Scheme 2.
Coupling of the CDI-activated carboxylic acids50,51 53–56 to the
arylpropylguanidines 44–52 gave the acylguanidines 57–78.27
Results and discussion
Chemistry
Synthesis of the acylguanidines. The amines and alcohols Tritylated heterocycles were deprotected under acidic condi-
required for the preparation of the arylpropylguanidines 44–52 tions yielding 79–86.
were synthesized as depicted in Scheme 1. Reduction of 6 with
Synthesis of the cyanoguanidines. The amines 92–106
LiAlH4 followed by aminomethylation in a Mannich reaction40 required for the preparation of the cyanoguanidines 107–133
gave the furan analog 8. The imidazolylpropanol 10 was were synthesized as recently reported.52 The synthesis of 107–
prepared by deprotonation of the methyl group in 9 with n-BuLi 133 was accomplished by analogy with a previously described
in THF and treatment with oxirane as an electrophile.41 Intro- procedure (Scheme 3).34 Diphenyl cyanocarbonimidate (87)53
duction of a three-membered carbon chain to the pyrazole core and the primary amines 88–89 gave the isourea intermediates
was performed by C–C coupling of the trityl-protected iodo- 90–91, which were treated with 92–106 in acetonitrile in a
pyrazole 11 with propargyl alcohol under Sonogashira condi- microwave oven to yield 107–133.54
tions42 using Pd(PPh3)2Cl2 and CuI as catalysts. Hydrogenation
over Pd/C (10%) provided the pyrazolylpropanol 14. The 57–86 were investigated for histamine receptor agonism or
Pharmacological results and discussion. The acylguanidines
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Scheme 1 Synthesis of the arylpropyl alcohols 8, 10, 14 and 20, and the pyridylpropylamines 27–29. Reagents and conditions: (i) LiAlH4 (2 eq.),
Et2O, overnight, 0 ꢂC / rt; (ii) NH(CH3)2$HCl (1.6 eq.), (CH2O)n (1.6 eq.), EtOH, overnight, reflux; (iii) oxirane (5 eq.), n-BuLi (1.1 eq.), THF,
overnight, ꢀ78 ꢂC / rt; (iv) TrCl (1 eq.), NEt3 (1.2 eq.), DCM, 12 h, 0 ꢂC / rt; (v) Pd(PPh3)2Cl2 (0.03 eq.), CuI (0.05 eq.), DIPA (4.5 eq.), propargyl
alcohol (1.1 eq.), DMF, 48 h, ꢀ15 ꢂC / rt; (vi) H2, Pd/C (10%) (cat.), MeOH, overnight, rt; (vii) TrCl (1 eq.), NEt3 (1 eq.), DCM, overnight, rt; (viii)
TMEDA (1 eq.), n-BuLi (1.1 eq.), DMF (0.9 eq.), THF, 12 h, ꢀ78 ꢂC; (ix) triethyl phosphonoacetate (1.2 eq.), NaH (60% dispersion in mineral oil) (1.2
eq.), THF, overnight, rt; (x) H2, Pd/C (10%) (cat.), EtOH/THF, overnight, rt; (xi) LiAlH4 (2 eq.), THF, 2 h, 0 ꢂC / reflux; (xii) phthalimide (1.1 eq.),
PPh3(1.1 eq.), DIAD (1.1 eq.), THF, overnight, 0 ꢂC / rt. (xiii) N2H4$H2O (6 eq.), EtOH, overnight, rt.
antagonism in steady-state GTPase assays using [32P] or [33P] (57 and 58), the agonistic potencies at the hH2,3,4Rs dramati-
radiolabeled GTP. These experiments were performed using cally decreased. However, in terms of antagonism at the hH2R,
membrane preparations of Sf9 insect cells expressing the these compounds (pKB ¼ 5.89) were comparable to the H2R
following proteins: hH1R plus regulator of G protein signalling antagonists cimetidine or ranitidine.59
4 (RGS4), hH2R-GsaS fusion protein, hH3R plus Gai2 plus Gb1g2
Replacing the imidazole ring in 1 with a 2-pyridyl ring resulted
plus RGS4 or hH4R-RGS19 fusion protein plus Gai2 plus Gb1g2 in an hH2R partial agonist (59) with a potency comparable to that
(Table 1).27,55,56 Selected compounds were additionally investi- of the endogenous ligand histamine (pEC50 ¼ 6.08, Emax ¼ 0.30).
gated for H1R and H2R activity at the guinea pig (gp) ileum and At the hH1R, this compound also behaved as a weak partial
the spontaneously beating guinea pig right atrium, respectively agonist. This is in agreement with data for the 2-pyridyl analogue
(Table 2). The cyanoguanidines 107–133 were investigated at the of histamine, betahistine, which is a weak agonist at the hH1R
hH1R as described above and at the other three HR subtypes in and hH2R.56,59 The bulky diphenylpropanoyl residue in 60 was not
[35S]GTPgS binding assays using membrane preparations of Sf9 tolerated in terms of agonistic potency. At the hH3R and hH4R, 59
cell expressing the hH2R-GsaS fusion protein, the hH3R plus and 60 were almost inactive. The 3- and 4-pyridyl analogues 61–64
Gai2 plus Gb1g2 or the hH4R plus Gai2 plus Gb1g2 (Table 3).57,58 displayed moderate antagonism at the hH2R and negligible
In the following agonistic potencies are expressed as pEC50 activities at the other HR subtypes.
(ꢀlog EC50) values. Intrinsic activities (a) refer to the maximal
Replacement of the imidazole ring by the 5-[(dimethylamino)-
response induced by the standard agonist histamine. methyl]furan-2-yl group, reminiscent of the H2R antagonist raniti-
Compounds identied to be inactive as agonists (a < 0.1 or dine, afforded hH2R antagonists (65–68): all prepared compounds
negative values, respectively, determined in the agonist mode) turned out to be superior to ranitidine (pKB ꢁ 6.10)59 at the hH2R,
were investigated in the antagonist mode. The pKB values of with the highest antagonist activity exhibited by the diphenylpro-
neutral antagonists and inverse agonists were determined from panoylguanidine 67 (pKB ¼ 7.03). 65–68 were weak inverse agonists
the concentration-dependent inhibition of the histamine- at the hH3R and almost inactive at the hH1R and hH4R.
induced increase in [35S]GTPgS binding or [g32P]GTP ([g33P]-
GTP) hydrolysis, respectively.
Apart from other heterocycles, isomers of the 1H-imidazol-4-yl
ring were investigated. The 1H-imidazol-1-yl isomer (69) was
Acylguanidines 57–86 (Tables 1 and 2). When the imidazole comparable with UR-AK24 (1) regarding intrinsic activity (Emax
:
ring in acylguanidines such as 1 was replaced by a phenyl ring 0.77 vs. 0.84) at the hH4R, but the potency was 65-fold lower
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Scheme 2 Synthesis of the NG-acylated arylpropylguanidines 57–86. Reagents and conditions: (i) benzyl chloroformate (3 eq.), NaOH (5 eq.),
H2O/DCM, 20 h, 0 ꢂC; (ii) Tf2O (1 eq.), NaH (60% dispersion in mineral oil) (2 eq.), chlorobenzene, overnight, ꢀ45 ꢂC / rt; (iii) PPh3 (1.5 eq.), DIAD
(1.5 eq.), THF, overnight, 0 ꢂC / rt; (iv) NEt3 (1 eq.), DCM, overnight, rt; (v) H2, Pd/C (10%) (cat.), MeOH, 3 h, rt; (vi) (a) CDI (1.2 eq.), NaH (60%
dispersion in mineral oil) (2 eq.), THF, 5 h, rt; (b) for trityl-protected intermediates 71–78: TFA (20%), DCM, 5 h, rt.
(pEC50: 6 vs. 7.82). The activities (69) at the other HRs were
Exchange of the imidazole ring in UR-AK24 by a 1H-pyrazol-
negligible (pKB < 5). However, the results for 69 suggest that, in 4-yl ring (83) resulted in a moderate decrease in potency and
contrast to other HR subtypes, an imidazole–NH group is efficacy at the hH2R (pEC50 ¼ 6.62, Emax ¼ 0.44). Interestingly,
obviously dispensible, though it is crucial to obtain highly this compound was virtually inactive at all other HRs, suggest-
potent hH4R agonists. As obvious from the diphenylpropanoyl ing the pyrazole ring to be an appropriate bioisostere of the
analogue 70, which is almost inactive at the hH4R, the hH4R imidazole ring to shi the receptor subtype selectivity toward
agonism strongly depends on the constitution of the acyl the hH2R. However, the bulky diphenylpropanoyl residue in 84
residue.
For the 1H-imidazol-2-yl isomers 79–82 similar pharmaco-
was deleterious for agonistic activity at the hH2R.
Compared to the pyrazole 83, the 1H-1,2,4-triazol-3-yl
logical activities at the hH4R were observed as for the 1H-imi- analogue 85 was more efficacious, but slightly less potent at
dazol-1-yl isomers 69 and 70. Both 3-arylbutanoylguanidines (79 the hH2R (pEC50 ¼ 6.13, Emax ¼ 0.66). In contrast to the pyr-
and 80) exhibited moderate partial agonistic potencies and low azole 84, the triazole analog 86 with a diphenylpropanoyl
intrinsic activities. Similar to the isomer 70, diarylpropanoyl moiety was an hH2R partial agonist with slightly higher
residues (81 and 82) abolished agonism at the hH4R. At the potency than 85 (pEC50 ¼ 6.39, Emax ¼ 0.42). This suggests that
other HR subtypes, 79–82 were very weak antagonists or inverse the acylguanidines containing a triazole or a pyrazole ring can
agonists.
adopt different binding modes at the hH2R. Like the pyrazoles
The results for the imidazole isomers suggest that, regarding 83 and 84, the triazoles 85 and 86 were almost inactive at the
agonism and compared to the other HR subtypes, the hH4R other HRs.
tolerates some modications in the arrangement of side chains
and nitrogen atoms in the heterocycle.
The basicity of pyrazole (pKa z 3)60 and triazole (pKa z 3)60 is
considerably lower than that of imidazole (pKa z 7).60 This may
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Scheme 3 Synthesis of the cyanoguanidines 107–133. Reagents and conditions: (i) 2-propanol, 1 h, rt; (ii) MeCN, microwave 150 ꢂC, 15 min.
be interpreted as a hint that the presence of a heterocycle, which close histamine analogues 2-(2-pyridyl)ethanamine and beta-
is positively charged at physiological pH value, is not required histine, which likewise display weak partial agonism at the
for hH2R activation. Moreover, the modication of the acyl guinea pig right atrium.61 Replacing the 1H-imidazol-4-yl by a
residue in triazolylalkylguanidines obviously harbours the 1H-pyrazol-4-yl ring (83 and 84) resulted in compounds with
potential of increasing H2R selectivity.
retained gpH2R partial agonistic activity. However, relative to
The results from isolated guinea pig organs were essen- UR-AK24 (1), the potency decreased by about one order of
tially in line with the data gained from recombinant human magnitude. In contrast to 83 and 84, the analogues bearing a
H1 and H2 receptors, but, in general, the guinea pig recep- 1H-1,2,4-triazol-3-yl ring (85, 86) and UR-AK24 were equieffica-
tors proved to be more sensitive than the human orthologs. cious, though 6-fold less potent at the guinea pig right atrium.
At the guinea pig ileum the investigated NG-acylated aryl- These ndings support the hypothesis that the 1H-1,2,4-triazol-
propylguanidines (Table 2) were moderate H1R antagonists. 3-yl ring is a potential bioisostere of the 1H-imidazol-4-yl moiety
Like at the hH2R, introduction of a phenyl (58), 3-pyridyl with respect to gpH2R affinity.
(61), 4-pyridyl (63), 5-[(dimethylamino)-methyl]furan-2-yl
Cyanoguanidines 107–133 (Table 3). The investigation of the
(65), 1H-imidazol-1-yl (69) and 1H-imidazol-2-yl moiety (79) synthesized cyanoguanidines for functional activity at the hH4R
resulted in a loss of agonistic efficacy at the gpH2R relative to revealed a high sensitivity even towards minor structural
compound 1 and yielded weak gpH2R antagonists. Remark- modications and corroborated, in this respect, previous
ably, the H2R antagonist activity of compound 65 was results.34 All cyanoguanidines bearing heterocycles other than
comparable to that of cimetidine at the guinea pig right imidazole revealed only negligible partial agonism or antago-
atrium.27
nism, or were even inactive at all four histamine receptor
In accordance with the results at the hH2R, the exchange of subtypes. The phenylthioethyl substituted aminopyrimidine
the 1H-imidazol-4-yl ring in UR-AK24 (1) by a 2-pyridyl ring (59) derivative 115 was the only compound with inverse agonistic
resulted in a gpH2R partial agonist with lower potency and activity in the lower micromolar range (pKB ꢁ 5.5) at both, the
efficacy than 1 (Emax ¼ 0.26). This tendency is reminiscent of the hH4R and the hH3R.
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Table 1 Potencies and efficacies of the prepared acylguanidines 57–86 at hH1R, hH2R, hH3R and hH4R in the steady-state GTPase assaya,b
hH1R
hH2R
hH3R
hH4R
Compound
pEC50 or (pKB)
N
pEC50 or (pKB)
N
pEC50 or (pKB)
N
3
2
5
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
pEC50 or (pKB)
N
8
2
6
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
2
3
2
2
2
3
Histamine
6.72 ꢃ 0.02 (ref. 28)
5.92 ꢃ 0.11 (ref. 28)
a: 1.00
7.17 (ref. 29)
a: 0.87
7.60 ꢃ 0.05
a: 1.00
7.92 ꢃ 0.11
a: 1.00
7.82 ꢃ 0.01
a: 0.84 ꢃ 0.06
(6.96 ꢃ 0.06)
a: ꢀ0.95 ꢃ 0.07
(<5)
n.d.
(<5)
n.d.
(<5)
n.d.
(<5)
n.d.
(<5)
n.d.
(<5)
n.d.
(<5)
a: 1.00
(<5)27
—
UR-AK24 (1)
8.60 ꢃ 0.11
a: 0.24 ꢃ 0.02
(7.01 ꢃ 0.08)
a: ꢀ0.71 ꢃ 0.6
(<5)
a: ꢀ0.19 ꢃ 0.03
(5.10 ꢃ 0.0)
a: ꢀ0.24 ꢃ 0.01
(<5)
a: ꢀ0.17 ꢃ 0.01
(5.35 ꢃ 0.04)
a: ꢀ0.44 ꢃ 0.01
(<5)
Thioperamide
n.d.
n.d.
57
58
59
60
61
62
63
64
65
66
67
68
69
70
79
80
81
82
83
84
85
86
(5.05 ꢃ 0.06)
a: ꢀ0.02 ꢃ 0.05
(5.26 ꢃ 0.03)
a: ꢀ0.01 ꢃ 0.01
(5.34 ꢃ 0.01)
a: 0.21 ꢃ 0.03
(5.41 ꢃ 0.02)
a: 0.10 ꢃ 0.02
(<5)
2
2
2
2
2
2
2
2
2
(5.89 ꢃ 0.04)
a: ꢀ0.10 ꢃ 0.00
(5.89 ꢃ 0.08)
a: ꢀ0.12 ꢃ 0.01
6.08 ꢃ 0.11
2
2
3
2
2
2
2
2
3
2
2
2
2
2
2
2
2
2
2
2
3
2
a: 0.30 ꢃ 0.01
(5.68 ꢃ 0.01)
a: ꢀ0.00 ꢃ 0.03
(5.27 ꢃ 0.0)
n.d.
a: ꢀ0.11 ꢃ 0.05
(6.14 ꢃ 0.08)
a: ꢀ0.16 ꢃ 0.05
(5.54 ꢃ 0.01)
a: 0.00 ꢃ 0.09
(6.14 ꢃ 0.01)
a: ꢀ0.12 ꢃ 0.06
(6.52 ꢃ 0.03)
a: ꢀ0.12 ꢃ 0.02
(6.51 ꢃ 0.12)
a: ꢀ0.12 ꢃ 0.02
(7.03 ꢃ 0.13
a: ꢀ0.16 ꢃ 0.02
(6.13 ꢃ 0.12)
a: ꢀ0.13 ꢃ 0.02
(<5)
a: ꢀ0.01 ꢃ 0.01
(5.04 ꢃ 0.04)
a: 0.06 ꢃ 0.04
(<5)
(<5)
a: ꢀ0.14 ꢃ 0.01
(<5)
a: 0.12 ꢃ 0.06
a: ꢀ0.07 ꢃ 0.06
(5.06 ꢃ 0.01)
a: ꢀ0.08 ꢃ 0.07
(5.92 ꢃ 0.01)
a: ꢀ0.64 ꢃ 0.00
(5.77 ꢃ 0.04)
a: ꢀ0.73 ꢃ 0.01
(5.89 ꢃ 0.07)
a: ꢀ0.65 ꢃ 0.01
(5.51 ꢃ 0.03)
a: ꢀ0.62 ꢃ 0.04
(<5)
n.d.
(<5)
n.d.
(<5)
n.d.
(<5)
(<5)
a: 0.08 ꢃ 0.07
(<5)
a: 0.04 ꢃ 0.01
n.d.
a: ꢀ0.14 ꢃ 0.05
(5.11 ꢃ 0.01)
a: ꢀ0.02 ꢃ 0.00
n.d.
2
(<5)
a: ꢀ0.16 ꢃ 0.09
(<5)
n.d.
6.00 ꢃ 0.13
a: 0.77 ꢃ 0.01
(<5)
(<5)
n.d.
(<5)
2
2
2
n.d.
a: ꢀ0.05 ꢃ 0.03
(5.82 ꢃ 0.03)
a: ꢀ0.07 ꢃ 0.02
(5.30 ꢃ 0.02)
a: 0.03 ꢃ 0.03
(5.26 ꢃ 0.14)
a: 0.04 ꢃ 0.00
(6.13 ꢃ 0.12)
a: ꢀ0.04 ꢃ 0.06
(5.19 ꢃ 0.11)
a: ꢀ0.00 ꢃ 0.00
6.62 ꢃ 0.11
(<5)
a: 0.01 ꢃ 0.01
a: ꢀ0.07 ꢃ 0.02
(5.41 ꢃ 0.11)
a: ꢀ0.32 ꢃ 0.02
(5.35 ꢃ 0.14)
a: ꢀ0.46 ꢃ 0.02
(5.47 ꢃ 0.04)
a: ꢀ0.33 ꢃ 0.00
(5.28 ꢃ 0.04)
a: ꢀ0.46 ꢃ 0.01
(<5)
n.d.
(<5)
5.54 ꢃ 0.19
a: 0.35 ꢃ 0.01
6.11 ꢃ 0.12
a: 0.50 ꢃ 0.04
(5.85 ꢃ 0.15)
a: ꢀ0.08 ꢃ 0.19
(<5)
n.d.
(<5)
n.d.
(<5)
a: 0.09 ꢃ 0.06
n.d.
(5.07 ꢃ 0.09)
a: 0.04 ꢃ 0.01
n.d.
2
(<5)
n.d.
(5.06 ꢃ 0.03)
a: 0.06 ꢃ 0.02
(<5)
n.d.
(<5)
a: 0.06 ꢃ 0.02
4
2
2
2
a: 0.44 ꢃ 0.01
(5.42 ꢃ 0.09)
a: 0.08 ꢃ 0.04
6.13 ꢃ 0.03
a: 0.04 ꢃ 0.01
(<5)
a: ꢀ0.02 ꢃ 0.01
(<5)
n.d.
Inactive
a: 0.66 ꢃ 0.02
6.39 ꢃ 0.01
a: ꢀ0.03 ꢃ 0.00
(<5)
Inactive
a: 0.42 ꢃ 0.01
a: ꢀ0.03 ꢃ 0.02
a
Steady-state GTPase activity in Sf9 insect cell membranes expressing the hH1R + RGS4, hH2R-GsaS fusion protein, hH3R + Gai2 + Gb1g2 + RGS4 or
hH4R-RGS19 fusion protein + Gai2 + Gb1g2 was determined as described in the ESI. N gives the number of independent experiments performed in
duplicate. b n.d.: not determined.
As expected, the compounds 107–112, bearing a methyl activity at the other HR subtypes. As reported previously, the
substituted imidazole ring, showed some activity at the H4R. phenylthioethyl residue confers higher potency at the H4R
The 2-methylimidazole derivatives 107 and 108 with a tetra- compared to a methyl substitution. Reducing the spacer
methylene chain connecting imidazole and cyanoguanidine chain length to three carbon atoms provides the hH4R partial
were weak inverse agonists at the H4R, devoid of noteworthy agonists 109 and 110 with pEC50 values around 6.3 and no
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Table 2 Pharmacological activities of selected compounds at the
guinea pig ileum (gpH1R) and the guinea pig right atrium (gpH2R)
superior to UR-PI376 in terms of H4R agonistic potency or
receptor subtype selectivity.
gpH1R
pA2
gpH2R
Conclusions
Compound
Na
—
4
pEC50b/(pA2)/[pD2’ ]c/ad
Na
>50
4
In summary, for most of the investigated acylguanidines the
replacement of the 1H-imidazol-4-yl ring with isomers or other
heterocycles resulted in considerably reduced potency and
efficacy at the hH2R, hH3R and hH4R. This underlines the
substantial contribution of an appropriate arrangement of the
nitrogen atoms in the heterocycle for binding to the H2R, H3R
and H4R and for stabilizing an active conformation of the H2R
and H4R. Strikingly, the imidazol-1-yl-propylguanidine deriv-
ative 69 displayed a comparable maximal response as its
isomer, reference compound UR-AK24 (1), at the H4R subtype,
although, the potency was about 50-fold lower. As these acyl-
guanidines were poorly active at the other HR subtypes and the
hH4R activity largely depended on the type of acyl residue,
further modications in this moiety appear promising with
respect to the development of more potent and selective hH4R
agonists.
Introduction of a 2-pyridyl (59 and 60), a 1H-pyrazol-4-yl
(83 and 84) or a 1H-1,2,4-triazol-3-yl (85 and 86) ring provided
compounds exhibiting partial to full agonist activity at the
hH2R and gpH2R. Except for the 2-pyridyl analogues, these
compounds had negligible activities at the other hHR
subtypes. In particular, the triazole ring was identied as a
promising bioisostere for the imidazole ring with respect
to H2R activity. At the gpH2R, the NG-acylated tri-
azolylpropylguanidines (85 and 86) were equiefficacious to
UR-AK24, but devoid of activities at the other hHR subtypes,
suggesting the 1H-1,2,4-triazol-3-yl ring as a potential bio-
isostere for the design of H2R selective ligands. 2-Amino-
thiazole analogues of acylguanidine-type H2R ligands are
described33,63 as highly selective agonists with higher poten-
cies compared to the triazole analogs. However, compared to
the aminothiazoles, the triazole ring is considered as relatively
stable against enzymatic oxidation.64 This may offer an alter-
native to improve the drug-like properties.
Histamine
—
6.00 ꢃ 0.10
a: 1.00 ꢃ 0.02
7.80 ꢃ 0.07
a: 0.99 ꢃ 0.02
(<4.5)
UR-AK24 (1)27
5.87 ꢃ 0.14
n.d.
UR-PG276 (3)
2
[< 4.5]
59
61
63
65
69
n.d.
6.71 ꢃ 0.04
a: 0.26 ꢃ 0.03
(<4.5)
[4.22 ꢃ 0.04]
(4.72 ꢃ 0.34)
[4.54 ꢃ 0.03]
(6.28 ꢃ 0.13)
a: 0e
3
n.d.
2
n.d.
2
5.52 ꢃ 0.06
5.95 ꢃ 0.05
18
18
2
(<4.5)
2
[4.16 ꢃ 0.05]
a: 0f
79
5.63 ꢃ 0.04
18
(4.90 ꢃ 0.16)
[4.44 ꢃ 0.15]
a: <10g
2
83
84
85
86
5.42 ꢃ 0.10
5.59 ꢃ 0.09
5.83 ꢃ 0.07
5.79 ꢃ 0.04
15
17
16
16
6.33 ꢃ 0.07
a: 0.54 ꢃ 0.03
6.44 ꢃ 0.11
a: 0.41 ꢃ 0.05
7.00 ꢃ 0.07h
a: 1.00 ꢃ 0.02
6.69 ꢃ 0.02
a: 0.83 ꢃ 0.06
3
3
3
3
Number of experiments. b pEC50 was calculated from the mean shi
DpEC50 of the agonist curve relative to the histamine reference curve
a
by equation: pEC50
represents the mean desensitization observed for control organs
¼
6.00 + 0.13 + DpEC50. Summand 0.13
when two successive curves for histamine were performed (0.13 ꢃ
0.02, N ¼ 16). The SEM given for pEC50 is the SEM calculated for
c
DpEC50
.
pD’2 values given in brackets for compounds producing a
signicant, concentration-dependent reduction of the maximal
d
response of histamine. Efficacy, maximal response, relative to the
maximal increase in heart rate induced by the reference compound
e
f
histamine.
Emax (histamine) at 10 mM: 0.68
ꢃ
0.01. Emax
g
(histamine) at 30 mM: 0.69 ꢃ 0.03. Emax (histamine) at 30 mM:
h
0.54 ꢃ 0.09. pA2 of cimetidine (10 mM, N ¼ 2): 6.32 ꢃ 0.06. For
The cyanoguanidines derived from OUP-16 and UR-PI376
revealed high sensitivity against both, replacement of the
heterocycle and minor structural modications such as
experimental details, cf. ESI.
agonistic activity at the other three histamine receptors. This methyl-substitution of the imidazole ring. None of the
is in agreement with the results for the amines 92 and 93.52 analogues showed improved potency and/or H4R selectivity
Compound 111, the carba analogue of cimetidine,61 was a compared to UR-PI376. Except for the heterocycle, the cya-
weak partial agonist at the hH4R (pEC50 ¼ 5.44) and the noguanidines are devoid of basic groups. Since previous
hH3R (pEC50 ¼ 5.97) and showed only very weak antagonistic studies revealed higher potency of H4R agonists with
properties at the hH1R and at the hH2R. This is in accor- retained basicity in the central structural motif, e.g. acyl-
dance with data reported for H2R antagonism at guinea pig guanidines, a combination of bioisosteric replacement of
right atrium and the rat uterus, where 111 was inferior to both, imidazole ring and cyanoguanidine moiety, should be
cimetidine by a factor of 6 to 10.61 The phenylthioethyl cya- considered in future ligand design.
noguanidine 112 was 15 times more potent as an hH4R
In conclusion, the presented data suggest alternative bio-
agonist than the methyl cyanoguanidine 111. With a pEC50 isosteric approaches, including the synthesis and pharmaco-
value of 6.61 at the H4R, the 5-methyl analogue of UR-PI376, logical evaluation of additional heterocyclic analogues of
compound 112, showed a more than 10-fold selectivity for the known histamine receptor ligands, with respect to retained/
H4R over the H3R and the other HR subtypes. Nevertheless, increased potency, improved receptor subtype selectivity and
none of the investigated hetarylalkylcyanoguanidines was drug-like properties.
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Table 3 Potencies and efficacies of the cyanoguanidines 107–133 at the hHR subtypes in the [35S]GTPgS assaya or the steady-state [32P]GTPase
assayb,c
hH1R
hH2R
hH3R
hH4R
Compound
Histamine
UR-PI376 (5)
Cimetidine
107
pEC50 or (pKB)
N
pEC50 or (pKB)
N
EC50 or (pKB)
N
3
EC50 or (pKB)
N
5
6.72 ꢃ 0.02 (ref. 28)
5.92 ꢃ 0.11 (ref. 28)
a: 1.00
7.89 ꢃ 0.07
a: 1.00
(6.14 ꢃ 0.02)
a: ꢀ0.52 ꢃ 0.05
n.d.
7.96 ꢃ 0.12
a: 1.00
7.43 ꢃ 0.04
a: 0.88 ꢃ 0.08
(<5)35
a: 1.00
(<5)34
a: 0.07
n.d.
(<5)34
2
3
a: 0.08
(5.77 ꢃ 0.11)62
a: ꢀ0.08 ꢃ 0.01
(<5)
(<5)
2
2
2
2
2
2
2
2
2
2
2
2
(<5)
2
2
2
2
2
2
(<5)
2
2
2
2
2
2
a: 0.01 ꢃ 0.03
a: 0.04 ꢃ 0.02
4.79 ꢃ 0.01
a: ꢀ0.05 ꢃ 0.02
(<5)
a: ꢀ0.13 ꢃ 0.08
a: ꢀ0.23 ꢃ 0.03
(6.21 ꢃ 0.04)
a: ꢀ0.24 ꢃ 0.11
6.26 ꢃ 0.02
a: 0.74 ꢃ 0.02
6.33 ꢃ 0.03
a: 0.40 ꢃ 0.07
5.44 ꢃ 0.04
a: 0.60 ꢃ 0.17
6.61 ꢃ 0.0
108
(<5.30)
(<5)
a: ꢀ0.01 ꢃ 0.03
Inactive
a: ꢀ0.47 ꢃ 0.04
(<5)
109
a: ꢀ0.02 ꢃ 0.01
a: ꢀ0.52 ꢃ 0.04
110
(<5.30)
(<5)
(<5)
a: 0.03 ꢃ 0.05
a: ꢀ0.05 ꢃ 0.02
(<5)
a: 0.04 ꢃ 0.01
(5.36 ꢃ 0.04)
a: ꢀ0.06 ꢃ 0.02
Inactive
a: ꢀ1.11 ꢃ 0.03
5.97 ꢃ 0.04
a: 0.23 ꢃ 0.03
(5.50 ꢃ 0.02)
a: ꢀ0.65 ꢃ 0.02
Inactive
111
(<5)
a: ꢀ0.03 ꢃ 0.02
(<5.30)
112
a: ꢀ0.03 ꢃ 0.01
a: 0.37 ꢃ 0.1
113
114
Inactive
2
2
2
2
2
2
Inactive
2
2
(<5)
(<5)
Inactive
Inactive
a: ꢀ0.02 ꢃ 0.01
a: ꢀ0.04 ꢃ 0.0
115
116
117
118
119
120
121
(<5)
2
2
2
2
2
2
2
(<5)
2
2
2
2
2
2
2
(5.54 ꢃ 0.01)
a: ꢀ1.03 ꢃ 0.01
(<5)
2
2
2
2
2
2
2
(5.43 ꢃ 0.09)
a: ꢀ0.83 ꢃ 0.06
Inactive
2
2
2
2
2
2
2
a: ꢀ0.02 ꢃ 0.04
(<5)
a: ꢀ0.07 ꢃ 0.01
(<5)
a: ꢀ0.01 ꢃ 0.03
a: ꢀ0.07 ꢃ 0.01
a: ꢀ0.26 ꢃ 0.03
a: 0.06 ꢃ 0.03
(<5)
(<5)
(<5)
(<5)
a: 0.03 ꢃ 0.01
Inactive
a: ꢀ0.08 ꢃ 0.00
<5
a: ꢀ0.42 ꢃ 0.06
Inactive
a: ꢀ0.05 ꢃ 0.04
Inactive
a: 0.31 ꢃ 0.02
(<5)
(<5)
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
a: 0.01 ꢃ 0.04
a: 0.03 ꢃ 0.02
(<5)
Inactive
a: ꢀ0.03 ꢃ 0.0
Inactive
(<5)
a: ꢀ0.01 ꢃ 0.04
Inactive
(<5)
122
123
Inactive
Inactive
2
2
2
2
Inactive
Inactive
2
2
Inactive
Inactive
2
2
a: ꢀ0.09 ꢃ 0.01
124
125
126
127
128
129
130
131
132
Inactive
Inactive
Inactive
2
2
2
2
2
2
2
2
2
(<5)
2
2
2
2
2
2
2
2
2
Inactive
Inactive
2
2
2
2
2
2
2
2
2
Inactive
Inactive
2
2
2
2
2
2
2
2
2
a: ꢀ0.02 ꢃ 0.0
(<5)
a: ꢀ0.05 ꢃ 0.00
Inactive
(<5)
(<5)
a: ꢀ0.03 ꢃ 0.04
a: ꢀ0.13 ꢃ 0.05
(<5)
(<5)
(<5)
(<5)
a: 0.02 ꢃ 0.03
a: ꢀ0.12 ꢃ 0.02
a: ꢀ0.21 ꢃ 0.02
(<5)
a: ꢀ0.10 ꢃ 0.01
(<5)
(<5)
Inactive
a: 0.03 ꢃ 0.03
(<5)
a: ꢀ0.10 ꢃ 0.03
a: ꢀ0.11 ꢃ 0.03
(<5)
(<5)
(<5)
a: ꢀ0.01 ꢃ 0.01
a: ꢀ0.13 ꢃ 0.01
a: ꢀ0.36 ꢃ 0.04
(<5)
a: ꢀ0.34 ꢃ 0.01
(<5)
Inactive
Inactive
a: ꢀ0.16 ꢃ 0.02
a: ꢀ0.11 ꢃ 0.03
(<5)
(<5)
(<5)
Inactive
a: 0.01 ꢃ 0.03
a: ꢀ0.08 ꢃ 0.02
a: ꢀ1.43 ꢃ 0.14
(<5)
(<5)
Inactive
Inactive
a: 0.03 ꢃ 0.02
a: ꢀ0.24 ꢃ 0.05
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Table 3 (Contd.)
hH1R
hH2R
hH3R
hH4R
Compound
pEC50 or (pKB)
N
pEC50 or (pKB)
N
EC50 or (pKB)
N
EC50 or (pKB)
N
133
(<5)
a: 0.01 ꢃ 0.02
2
(<5)
2
(5.14 ꢃ 0.01)
2
(<5)
2
a: ꢀ0.11 ꢃ 0.01
a: ꢀ0.71 ꢃ 0.03
a: ꢀ0.09 ꢃ 0.05
a
Functional [35S]GTPgS binding assay with membrane preparations of Sf9 cells expressing the hH3R + Gai2 + Gb1g2 or the hH4R + Gai2 + Gb1g2 or
the hH2R-Gsas fusion protein were performed as described in the ESI. b Steady-state GTPase activity in Sf9 cell membranes expressing the hH1R +
RGS4 was determined as described under Pharmacological methods. c Reaction mixtures contained ligands at a concentration range from 1 nM to 1
mM as appropriate to generate saturated concentration/response curves. N gives the number of independent experiments performed in duplicate.
The intrinsic activity (a) of histamine was set to 1.00 and a values of other compounds were referred to this value. The a values of neutral antagonists
and inverse agonists were determined at a concentration of 10 mM. The pKB values of neutral antagonists and inverse agonists were determined in
the antagonist mode versus histamine as the agonist.
12 T. Nguyen, D. A. Shapiro, S. R. George, V. Setola, D. K. Lee,
Acknowledgements
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Karin Schadendorf, Gertraud Wilberg and Astrid Seefeld for
expert technical assistance. This work was supported by the
Graduate Training Program (Graduiertenkolleg) GRK 760 of the
Deutsche Forschungsgemeinscha and the COST program
BM0806 (H4R network) of the European Union.
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