- Histamine H3 receptor antagonists with peptidomimetic (keto)piperazine structures to inhibit Aβ oligomerisation
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Alzheime?s disease (AD) is the most prominent neurodegenerative disorder with high medical need. Protein-protein-interactions (PPI) interactions have a critical role in AD where β-amyloid structures (Aβ) build toxic oligomers. Design of disease modifying multi target directed ligand (MTDL) has been performed, which disable PPI on the one hand and on the other hand, act as procognitive antagonists at the histamine H3 receptor (H3R). The synthetized compounds are structurally based on peptidomimetic amino acid-like structures mainly as keto, diketo-, or acyl variations of a piperazine moiety connected to an H3R pharmacophore. Most of them showed low nanomolar affinities at H3R and some with promising affinity to Aβ-monomers. The structure–activity relationships (SAR) described offer new possibilities for MTDL with an optimized profile combining symptomatic and potential causal therapeutic approaches in AD.
- Falkenstein, Markus,Reiner-Link, David,Zivkovic, Aleksandra,Gering, Ian,Willbold, Dieter,Stark, Holger
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- INDENOISOQUINOLINONE DERIVATIVES, MANUFACTURING METHOD AND MEDICAL USE THEREOF
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Indenoisoquinolinone derivatives (I), the manufacturing method and the medical use thereof, which belong to pharmaceutical chemistry and organic chemistry field, are disclosed. These compounds can be used for treating several medical symptoms related to postmenopausal syndrome, uterine fibers deterioration and aortic smooth muscle cells proliferation, especially ER-(+) depend breast cancer. Meanwhile, these compounds can also be used for treating glioma and lung cancer, and have inhibiting effect on tumor metastasis effect on tumor metastasis.
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Paragraph 0054; 0055
(2013/04/13)
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- Bodilisant - A novel fluorescent, highly affine histamine H3 receptor ligand
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A piperidine-based lead structure for the human histamine H3 receptor (hH3R) was coupled with the BODIPY fluorophore and resulted in a strong green fluorescent (quantum yield, 0.92) hH3R ligand with affinity in the nanomolar concentration range (Ki hH3R = 6.51 ± 3.31 nM), named Bodilisant. Screening for affinities at histamine and dopamine receptor subtypes showed high hH3R preference. Bodilisant was used for visualization of hH3R in hH3R overexpressing HEK-293 cells with fluorescence confocal laser scanning microscopy. In addition, in native human brain tissues, Bodilisant showed clear and displaceable images of labeled hH3R.
- Tomasch, Miriam,Schwed, J. Stephan,Paulke, Alexander,Stark, Holger
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supporting information
p. 269 - 273
(2013/03/28)
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- First metal-containing histamine H3 receptor ligands
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Iron-containing ligands targeting the human histamine H3 receptor (hH3R) were prepared. The compounds contain ferrocene sandwich complexes coupled via different linkers to a basic hH3R antagonist/inverse agonist pharmacophore. In a click chemistry approach, a triazole was successfully inserted as a new linking element. Two ferrocenylmethylamines and a ferrocenyltriazole were the most affine hH 3R ligands within this series, showing receptor binding in the nano- and subnanomolar concentration range.
- Sander, Kerstin,Kottke, Tim,Hoffend, Claas,Walter, Miriam,Weizel, Lilia,Camelin, Jean-Claude,Ligneau, Xavier,Schneider, Erich H.,Seifert, Roland,Schwartz, Jean-Charles,Stark, Holger
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supporting information; experimental part
p. 2578 - 2581
(2010/10/02)
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- Kojic acid derivatives as histamine H3 receptor ligands
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The histamine H3 receptor (H3R) is a promising target in the development of new compounds for the treatment of mainly centrally occurring diseases. However, emerging novel therapeutic concepts have been introduced and some indications in the H3R field, e.g. migraine, pain or allergic rhinitis, might take advantage of peripherally acting ligands. In this work, kojic acid-derived structural elements were inserted into a well established H3R antagonist/inverse agonist scaffold to investigate the bioisosteric potential of γ-pyranones with respect to the different moieties of the H3R pharmacophore. The most affine compounds showed receptor binding in the low nanomolar concentration range. Evaluation and comparison of kojic acid-containing ligands and their corresponding phenyl analogues (3-7) revealed that the newly integrated scaffold greatly influences chemical properties (S Log P, topological polar surface area (tPSA)) and hence, potentially modifies the pharmacokinetic profile of the different derivatives. Benzyl-1-(4-(3-(piperidin-1-yl)propoxy)phenyl)methanamine ligands 3 and 4 belong to the centrally acting diamine-based class of H3R antagonist/inverse agonist, whereas kojic acid analogues 6 and 7 might act peripherally. The latter compounds state promising lead structures in the development of H3R ligands with a modified profile of action.
- Sander, Kerstin,Kottke, Tim,Weizel, Lilia,Stark, Holger
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experimental part
p. 1353 - 1361
(2010/12/25)
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- Histamine H3-receptor ligands and their therapeutic application
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The present patent application concerns new compounds of formula (I) with R 1 and R 2 taken together with the nitrogen atom to which they are attached, form a saturated nitrogen-containing ring, A is a saturated C1-4 alkylene and B a C3-4 alkylene or alkenylene chain; their preparation and their use as a H3 receptor ligand for treating e.g. CNS disorders like Alzheimer's disease.
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Page/Page column 13
(2010/11/24)
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- Search for histamine H3 receptor antagonists with combined inhibitory potency at Nτ-methyltransferase: Ether derivatives
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With the recent development of new hybrid compounds having histamine H 3 receptor antagonist with combined histamine Nτ- methyltransferase (HMT) inhibitory potency an innovative approach was described in the research of novel lead compounds modulating histaminergic neurotransmission. Several compounds containing an ether moiety derived from the recently published 4-(3-piperidinopropoxy)phenylaminoquinoline derivatives (like FUB 836), were synthesized in this study and tested for their affinity at cloned human histamine H3 (hH3) receptors and on the inhibition of rat HMT. Besides different heterocycles, e.g. nitro- or amino-substituted pyridines, quinolines, benzothiazole or pyrroline, three classes of compounds were produced: heteroaromatic 3-piperidinopropyl ethers, keto- or imino-substituted 4-(3-piperidinopropyl)phenyl ethers and 4-(3-piperidinopropyl)phenyl ethers with substituted (alkyl)aminopyridines. Whereas the (3-piperidinopropoxy)heterocycles showed only moderate activities on both test models, the 4-(3-piperidinopropoxy)phenyl derivatives were identified as potent histamine H3 receptor ligands and/or HMT inhibitors. Ki values up to 0.42 nM were found for the affinity to the hH 3 receptor. HMT inhibitory potency was identified with IC 50 values about 0.3 μM for the most potent compounds in this series. Comparison of the pyridine-containing derivatives to recently published quinoline analogues showed a decrease in potencies for the pyridines. The dual activity, H3 receptor affinity and HMT inhibition, was moderate to good. For all compounds affinities at hH3 receptors were higher than their inhibitory HMT potencies. The described new histamine H3 receptor antagonists with an ether moiety represent a further promising step in our investigations for a dual activity.
- Apelt,Grassmann,Ligneau,Pertz,Ganellin,Arrang,Schwartz,Schunack,Stark, Holger
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- Search for histamine H3 receptor ligands with combined inhibitory potency at histamine N-methyltransferase: ω- piperidinoalkanamine derivatives
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In an effort to design new hybrid compounds with dual properties, i.e. binding affinity at histamine H3 receptors and inhibitory potency at the catabolic enzyme histamine Nτ-methyltransferase (HMT), a novel series of 1-substituted piperidine derivatives was synthesized. This alicyclic heterocycle is structurally linked via aminoalkyl spacers of variable lengths to additional aromatic carbo- or heterocycles. These new hybrid drugs were pharmacologically evaluated regarding their binding affinities at recombinant human H3 receptors, stably expressed in CHO cells, and in a functional assay for their inhibitory potencies at rat kidney HMT. All compounds investigated proved to be H3 receptor ligands with binding affinities in the micro- to nanomolar concentration range despite significant differences in the type of the aromatic moiety introduced. The most potent compound in this series was the quinoline derivative 20 (Ki = 5.6 nM). Likewise, all new ligands studied showed impressive HMT inhibitory activities. Here, compounds 5, 10, 14, and 18-20 exhibited submicromolar potencies (IC50 = 0.061 -0.56 μM). The aminomethylated quinoline 19 showed almost the same, well balanced nanomolar activities on both targets. In this study, new hybrid compounds with a dual mode biological action were developed. These pharmacological agents are valuable leads for further development and candidates for treatment of histamine-dependent disorders.
- Grassmann, Sven,Apelt, Joachim,Ligneau, Xavier,Pertz, Heinz H.,Arrang, Jean-Michel,Ganellin, C. Robin,Schwartz, Jean-Charles,Schunack, Walter,Stark, Holger
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p. 533 - 545
(2007/10/03)
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- α1b-adrenergic receptor antagonists
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There are provided compounds represented by the general formula (I): [wherein Ar is indole etc., R1is hydrogen etc., B is bond, or B—N—R1forms a ring structure and is piperidine etc., n is 0, 1, etc., A is trimethylene, butylene, etc., Q is piperidine, isoindoline, etc.], or pharmacologically acceptable acid addition salts thereof, and α1B adrenoceptor antagonists composed of these substances. The invented compounds are antagonists having high affinity for α1B adrenoceptor and are useful as pharmaceutical agents for use in prophylaxis/therapy of diseases (e.g., hypertension) in which α1B adrenoceptor is involved or as pharmacological tools for elucidation of physiological activities mediated by α1B adrenoceptor.
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Page/Page column 76-77
(2010/11/30)
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- Development of a new class of nonimidazole histamine H3 receptor ligands with combined inhibitory histamine N-methyltransferase activity
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In search of novel ways to enhance histaminergic neurotransmission in the central nervous system, a new class of nonimidazole histamine H3 receptor ligands were developed that simultaneously possess strong inhibitory activity on the main histamine metabolizing enzyme, histamine N-methyltransferase (HMT). The novel compounds contain an aminoquinoline moiety, which is an important structural feature for HMT inhibitory activity, connected by different spacers to a piperidino group (for H3 receptor antagonism). Variation of the spacer structure provides two different series of compounds. One series, having only an alkylene spacer between the basic centers, led to highly potent HMT inhibitors with moderate to high affinity at human histamine H3 receptors. The second series possesses a p-phenoxypropyl spacer, which may be extended by another alkylene chain. This latter series also showed strong inhibitory activity on HMT, and in most cases, the H3 receptor affinity even surpassed that of the first series. One of the most potent compounds with this dual mode of action is 4-(4-(3-piperidinopropoxy)phenylamino)quinoline (34) (hH3, Ki = 0.09 nM; HMT, IC50 = 51 nM). This class of compounds showed high antagonist potency and good H3 receptor selectivity in functional assays in guinea pig on H1, H2, and H3 receptors. Because of low or missing in vivo activity of two selected compounds, the proof of concept of these valuable pharmacological tools for the supposed superior overall enhancing effect on histaminergic neurotransmission failed to appear hitherto.
- Apelt, Joachim,Ligneau, Xavier,Pertz, Heinz H.,Arrang, Jean-Michel,Ganellin, C. Robin,Schwartz, Jean-Charles,Schunack, Walter,Stark, Holger
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p. 1128 - 1141
(2007/10/03)
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- Nitro, amino and aroylamino-N-phenylpyridinamines in a process for preparing pyrido[1,4]benzodiazepines
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Nitro, amino and aroylamino-N-phenylpyridinamines as chemical intermediates and/or having antidepressant activity having the formula STR1 wherein R3 is nitro, amino or aroylamino, and Q is hydrogen, --NR1 R2 or halogen are disclosed in a process for preparing pyrido[1,4]benzodiazepines.
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- [2-[(Nitropyridinyl)amino]phenyl]arymethanones
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[2-[(Nitropyridinyl)amino]phenyl]arylmethanones as chemical intermediates and/or having antidepressant activity having the formula: STR1 wherein: B is carbonyl, thioxomethyl, ketal or thioketal, R is hydrogen or -alk1 -Q, Q is hydrogen, --NR1 R2 or halogen are disclosed in a process for preparing pyrido[1,4]benzodiazepines.
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