共查询到20条相似文献,搜索用时 62 毫秒
1.
Katarzyna Szczepańska Tadeusz Karcz Magdalena Kotańska Agata Siwek Kamil J. Kuder Gniewomir Latacz Szczepan Mogilski Stefanie Hagenow Annamaria Lubelska Michał Sobolewski Holger Stark Katarzyna Kieć-Kononowicz 《Bioorganic & medicinal chemistry》2018,26(23-24):6056-6066
As a continuation of our search for novel histamine H3 receptor ligands, a series of new acetyl and propionyl phenoxyalkylamine derivatives (2–25) was synthesized. Compounds with three to four carbon atoms alkyl chain spacer, composed of six various 4N-substituted piperazine moieties were evaluated for their binding properties at human histamine H3 receptors (hH3R). In vitro test results proved the 4-pyridylpiperazine moiety as crucial element for high hH3R affinity (hH3R Ki?=?5.2–115?nM). Moreover introduction of carbonyl group containing residues in the lipophilic part of molecules instead of branched alkyl substituents resulted in increased affinity in correlation to previously described series, whereas propionyl derivatives showed slightly higher affinities than those of acetyl (16 and 22vs.4 and 10; hH3R Ki?=?5.2 and 15.4?nM vs. 10.2 and 115?nM, respectively). These findings were confirmed by molecular modelling studies, demonstrating multiple ligand-receptor interactions. Furthermore, pharmacological in vivo test results of compound 4 clearly indicate that it may affect the amount of calories consumed, thus act as an anorectic compound. Likewise, its protective action against hyperglycemia and the development of overweight has been shown. In order to estimate drug-likeness of compound 4, in silico and experimental evaluation of metabolic stability in human liver microsomes was performed. 相似文献
2.
《Bioorganic & medicinal chemistry letters》2014,24(19):4759-4762
5-HT1AR agonist or partial agonists are established drug candidates for psychiatric and neurological disorders. We have reported the synthesis and evaluation of a series of high affinity 5-HT1AR partial agonist PET imaging agents with greater selectivity over α-1AR. The characteristic of these molecules are 3,5-dioxo-(2H,4H)-1,2,4-triazine skeleton tethered to an arylpiperazine unit through an alkyl side chain. The most potent 5-HT1AR agonistic properties were found to be associated with the molecules bearing C-4 alkyl group as the linker. Therefore development of 3,5-dioxo-(2H,4H)-1,2,4-triazine bearing arylpiperazine derivatives may provide high affinity selective 5-HT1AR ligands. Herein we describe the synthesis and evaluation of the binding properties of a series of arylpiperazine analogues of 3,5-dioxo-(2H,4H)-1,2,4-triazine. 相似文献
3.
《Bioorganic & medicinal chemistry》2016,24(2):53-72
A series of twenty new chlorophenoxyalkylamine derivatives (9–28) was synthesized and evaluated on their binding properties at the human histamine H3 receptor (hH3R). The spacer alkyl chain contained five to seven carbon atoms. The highest affinities have shown the 4-chloro substituted derivatives 10 and 25 (Ki = 133 and 128 nM, respectively) classified as antagonists in cAMP accumulation assay (EC50 = 72 and 75 nM, respectively). Synthesized compounds were also evaluated for anticonvulsant activity in Antiepileptic Screening Program (ASP) at National Institute of Neurological Disorders and Stroke (USA). Two compounds (4-chloro substituted derivatives: 20 and 26) were the most promising and showed in the MES seizure model in rats (after ip administration) ED50 values of 14 mg/kg and 13.18 mg/kg, respectively. Protective indexes (PI = TD50/ED50) were 3.2 for 20 and 3.8 for 26. Moreover, molecular modeling and docking studies were undertaken to explain affinity at hH3R of target compounds, and the experimentally and in silico estimation of properties like lipophilicity and metabolism was performed. Antiproliferative effects have been also investigated in vitro for selected compounds (10 and 25). These compounds neither possessed significant antiproliferative and antitumor activity, nor modulated CYP3A4 activity up to concentration of 10 μM. 相似文献
4.
《Bioorganic & medicinal chemistry letters》2014,24(10):2236-2239
Several hH3R antagonists/inverse agonists entered clinical phases for a broad spectrum of mainly centrally occurring diseases. Nevertheless, many promising candidates failed due to their pharmacokinetic profile, mostly because of their strong lipophilicity and their dibasic character. Analysis of previously, as potential PET ligands synthesized compounds (ST-889, ST-928) revealed promising results concerning physicochemical properties and drug-likeness. Herein, the synthesis, the evaluation of the binding properties at the hH3R and the estimation of different physicochemical and drug-likeness properties of further novel benzylpiperidine variations on H3R antagonists is described. Due to the introduction of various small hydrophilic moieties in the structure, drug-likeness parameters have been improved. For instance, compound 12 (ST-1032) showed in addition to high affinity at the H3R (pKi (hH3R) = 9.3) c log S, c log P, LE, LipE, and LELP values of −2.48, 2.18, 0.44, 7.14, and 4.95, respectively. Also, the keto derivative 5 (ST-1703, pKi (hH3R) = 8.6) revealed LipE and LELP values of 5.25 and 6.84, respectively. 相似文献
5.
Iou-Jiun Kang Li-Wen Wang Chung-Chi Lee Yen-Chun Lee Yu-Sheng Chao Tsu-An Hsu Jyh-Haur Chern 《Bioorganic & medicinal chemistry letters》2009,19(7):1950-1955
A series of thiourea derivatives were synthesized and their antiviral activity was evaluated in a cell-based HCV subgenomic replicon assay. SAR studies revealed that the chain length and the position of the alkyl linker largely influenced the in vitro anti-HCV activity of this class of potent antiviral agents. Among this series of compounds synthesized, the thiourea derivative with a six-carbon alkyl linker at the meta-position of the central phenyl ring (10) was identified as the most potent anti-HCV inhibitor (EC50 = 0.047 μM) with a selectivity index of 596. 相似文献
6.
Kamil J. Kuder Dorota Łażewska Maria Kaleta Gniewomir Latacz Tim Kottke Agnieszka Olejarz Tadeusz Karcz Andrzej Fruziński Katarzyna Szczepańska Janina Karolak-Wojciechowska Holger Stark Katarzyna Kieć-Kononowicz 《Bioorganic & medicinal chemistry》2017,25(10):2701-2712
As a continuation of our search for novel histamine H3 receptor ligands a series of twenty new tert-amyl phenoxyalkylamine derivatives (2–21) was synthesized. Compounds of four to eight carbon atoms spacer alkyl chain were evaluated on their binding properties at human histamine H3 receptor (hH3R). The highest affinities were observed for pentyl derivatives 6–8 (Ki = 8.8–23.4 nM range) and among them piperidine derivative 6 with Ki = 8.8 nM. Structures 6, 7 were also classified as antagonists in cAMP accumulation assay (with EC50 = 157 and 164 nM, respectively). Moreover, new compounds were also evaluated for anticonvulsant activity in Antiepileptic Screening Program (ASP) at National Institute of Neurological Disorders and Stroke (USA). Seven compounds (2–4, 9, 11, 12 and 20) showed anticonvulsant activity at maximal electroshock (MES) test in the dose of 30 mg/kg at 0.5 h. In the subcutaneous pentetrazole (scMET) test compound 4 showed protection at 100 and 300 mg/kg dose at mice, however compounds showed high neurotoxicity in rotarod test at used doses. Also, molecular modeling studies were undertaken, to explain affinity of compounds at hH3R (taking into the consideration X-ray analysis of compound 18). In order to estimate “drug-likeness” of selected compounds in silico and experimental evaluation of lipophilicity, metabolic stability and cytotoxicity was performed. 相似文献
7.
Dorota Łażewska Szczepan Mogilski Stefanie Hagenow Kamil Kuder Monika Głuch-Lutwin Agata Siwek Małgorzata Więcek Maria Kaleta Ulla Seibel Armin Buschauer Barbara Filipek Holger Stark Katarzyna Kieć-Kononowicz 《Bioorganic & medicinal chemistry》2019,27(7):1254-1262
This study focuses on the design, synthesis, molecular modeling and biological evaluation of a novel group of alkyl-1,3,5-triazinyl-methylpiperazines. New compounds were synthesized and their affinities for human histamine H4 receptor (hH4R) were evaluated. Among them, 4-(cyclohexylmethyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (14) exhibited hH4R affinity with a Ki of 160?nM and behaved as antagonist in functional assays: the cellular aequorin-based assay (IC50?=?32?nM) and [35S]GTPγS binding assay (pKb?=?6.67). In addition, antinociceptive activity of 14 in vivo was observed in Formalin test (in mice) and in Carrageenan-induced acute inflammation test (in rats). 相似文献
8.
K. Lutsenko S. Hagenow A. Affini D. Reiner H. Stark 《Bioorganic & medicinal chemistry letters》2019,29(19):126612
The irreversible monoamine oxidase B (MAO B) inhibitor rasagiline has been described with multiple disease modifying effects in vitro on models of Parkinson’s disease. The combination of this established drug to recently developed histamine H3 receptor (H3R) antagonist elements gives new impetus to the design of multitargeting ligands. Surprisingly, the 5-substituted 3-piperidinopropyloxy rasagiline derivative 1 was more potent on both targets than its 6-substituted isomer. It showed nanomolar affinities at the desired targets (MAO B IC50 = 256 nM; hH3R Ki = 2.6 nM) with a high preference over monoamine oxidase A (MAO A) and negligible affinity at histamine H1, H4, dopamine D2, D3 receptors or acetyl-/butyrylcholinesterases. 相似文献
9.
Kinga Ostrowska Dawid Grzeszczuk Monika Głuch-Lutwin Anna Gryboś Agata Siwek Anna Leśniak Mariusz Sacharczuk Bartosz Trzaskowski 《Bioorganic & medicinal chemistry》2018,26(2):527-535
In this work we describe the synthesis, docking studies and biological evaluation of a focused library of novel arylpiperazinyl derivatives of 8-acetyl-7-hydroxy-4-methylcoumarin. The new compounds were screened for their 5-HT1A and 5-HT2A receptor affinity. Among the evaluated compounds, six displayed high affinities to 5-HT1A receptors (4a-0.9?nM, 6a-0.5?nM, 10a-0.6?nM, 3b-0.9?nM, 6b-1.5?nM, 10b-1?nM). Compound 6a and 10a bearing a bromo- or methoxy- substituent in ortho position of the piperazine phenyl ring, were identified as potent antagonists of the 5-HT1A receptors. In the tail suspension test, mice injected with 6a showed a dose-dependent increase in depressive-like behavior that was related to a decrease in locomotor activity. Compound 10a did not decrease or prolong immobility time nor did it affect home cage activity. Molecular docking studies using 5-HT1A and 5-HT2A homology models revealed structural basis of the high affinity of ortho-substituted derivatives and subtle changes in amino acid interactions patterns depending on the length of the alkyl linker. 相似文献
10.
Ling-Jie Gao J. Stephan Schwed Lilia Weizel Steven De Jonghe Holger Stark Piet Herdewijn 《Bioorganic & medicinal chemistry letters》2013,23(1):132-137
Starting from a known H4R ligand based on a pyrimidine skeleton, a series of novel analogues based on a pyrrolo[2,3-d]pyrimidine scaffold have been prepared. Whereas the original pyrimidine congener shows good affinity at hH4R (Ki = 0.5 μM), its lacks selectivity with a Ki value for the hH3R of 1 μM. Within the newly synthesized pyrrolo[2,3-d]pyrimidines, several congeners show Ki values of less than 1 μM at the hH4R and show a much improved selectivity profile. Therefore, these series represent an interesting starting point for the discovery of novel hH4R ligands. 相似文献
11.
Christian Espinosa-Bustos Annika Frank Sandra Arancibia-Opazo Cristian O. Salas Angelica Fierro Holger Stark 《Bioorganic & medicinal chemistry letters》2018,28(17):2890-2893
This work describes the microwave assisted synthesis of twelve novel histamine H3 receptor ligands. They display pyrrolo[2,3-d]pyrimidine derivatives with rigidized aliphatic amines as warheads. The compounds were screened for H3R and H4R binding affinities in radioligand displacement assays and the most potent compounds were evaluated for H3R binding properties in vitro and in docking studies. The combination of a rigidized H3R warhead and the pyrrolo[2,3-d]pyrimidine scaffold resulted in selective activity at the H3 receptor with a pKi value of 6.90 for the most potent compound. A bipiperidine warhead displayed higher affinity than a piperazine or morpholine motif, while a naphthyl moiety in the arbitrary region increased affinity compared to a phenyl derivative. The compounds can be starting points for novel, simply synthesized histamine H3 receptor ligands. 相似文献
12.
Rohit Bhat James A. Fishback Rae R. Matsumoto Jacques H. Poupaert Christopher R. McCurdy 《Bioorganic & medicinal chemistry letters》2013,23(17):5011-5013
Herein we report the SAR study which involved structural modifications to the linker length, aryl substitution and alkylamine ring size of the benzo[d]thiazol-2(3H)one based sigma receptor (σ) ligands. Many compounds in this series displayed low nanomolar affinity for the σ receptor subtypes. In particular, 8a showed high affinity (σ-1 Ki = 4.5 nM) for σ-1 receptors and moderately high selectivity (483-fold) over σ-2 receptors. 相似文献
13.
Nirogi R Dwarampudi A Kambhampati R Bhatta V Kota L Shinde A Badange R Jayarajan P Bhyrapuneni G Dubey PK 《Bioorganic & medicinal chemistry letters》2011,21(15):4577-4580
A series of N1-arylsulfonyl-3-(pyrrolidin-3-yl)-1H-indole and N1-arylsulfonyl-3-(4-chloro-2,5-dihydro-1H-pyrrol-3-yl)-1H-indole derivatives (tryptamine derivatives with rigidized side chain) have been prepared and tested for their binding affinity to 5-HT6 receptor. Several compounds displayed potent binding affinity for the 5-HT6 receptor when tested in in vitro binding assay. The primary SAR indicates that rigidification of dimethylamino alkyl chain at C3 of indole carbon maintains the binding affinity to 5-HT6R. The lead compound N1-benzenesulfonyl-3-(4-chloro-1-methyl-2,5-dihydro-1H-pyrrol-3-yl)-1H-indole, 10a (Kb = 0.1 nM) has shown excellent in vitro affinity and was active in animal models of cognition like NORT and water maze. 相似文献
14.
Bassem Sadek Safa Shehab Małgorzata Więcek Dhanasekaran Subramanian Mohamed Shafiullah Katarzyna Kieć-Kononowicz Abdu Adem 《Bioorganic & medicinal chemistry letters》2013,23(17):4886-4891
Ligands targeting central histamine H3 receptors (H3Rs) for epilepsy might be a promising therapeutic approach. Therefore, the previously described and structurally strongly related imidazole-based derivatives belonging to carbamate class with high H3R in vitro affinity, in-vivo antagonist potency, and H3R selectivity profile were investigated on their anticonvulsant activity in maximal electroshock (MES)-induced and pentylenetetrazole (PTZ)-kindled seizure models in Wistar rats. The effects of systemic injection of H3R ligands 1–13 on MES-induced and PTZ-kindled seizures were screened and evaluated against the reference antiepileptic drug (AED) Phenytoin (PHT) and the standard histamine H3R inverse agonist/antagonist Thioperamide (THP) to determine their potential as new antiepileptic drugs. Following administration of the H3R ligands 1–13 (5, 10 and 15 mg/kg, ip) there was a significant dose dependent reduction in MES-induced seizure duration. The protective action observed for the pentenyl carbamate derivative 4, the most protective H3R ligand among 1–13, was significantly higher (P <0.05) than that of standard H3R antagonist THP, and was reversed when rats were pretreated with the selective H3R agonist R-(α)-methyl-histamine (RAMH) (10 mg/kg), or with the CNS penetrant H1R antagonist Pyrilamine (PYR) (10 mg/kg). In addition, subeffective dose of H3R ligand 4 (5 mg/kg, ip) significantly potentiated the protective action in rats pretreated with PHT (5 mg/kg, ip), a dose without appreciable protective effect when given alone. In contrast, pretreatment with H3R ligand 4 (10 mg/kg ip) failed to modify PTZ-kindled convulsion, whereas the reference drug PHT was found to fully protect PTZ-induced seizure. These results indicate that some of the investigated imidazole-based H3R ligands 1–13 may be of future therapeutic value in epilepsy. 相似文献
15.
Mizuki Watanabe Takaaki Kobayashi Yoshihiko Ito Hayato Fukuda Shizuo Yamada Mitsuhiro Arisawa Satoshi Shuto 《Bioorganic & medicinal chemistry letters》2018,28(23-24):3630-3633
We previously designed and synthesized a series of histamine analogues with an imidazolylcyclopropane scaffold and identified potent non-selective antagonists for histamine H3 and H4 receptor subtypes. In this study, to develop H4 selective ligands, we newly designed and synthesized cyclopropane-based derivatives having an indole, benzimidazole, or piperazine structure, which are components of representative H4 selective antagonists such as JNJ7777120 and JNJ10191584. Among the synthesized derivatives, imidazolylcyclopropanes 12 and 13 conjugated with a benzimidazole showed binding affinity to the H3 and H4 receptors comparable to that of a well-known non-selective H3/H4 antagonist, thioperamide. These results suggest that the binding modes of the cyclopropane-based H3/H4 ligands in the H4 receptor can be different from those of the indole/benzimidazole-piperazine derivatives. 相似文献
16.
Katsumi Kubota Hirotaka Kurebayashi Hirotaka Miyachi Masanori Tobe Masako Onishi Yoshiaki Isobe 《Bioorganic & medicinal chemistry letters》2009,19(10):2766-2771
A series of phenothiazine carboxylic acid derivatives, having 6-amino-pyrimidine-2,4(1H,3H)-dione moiety via a appropriate linker, were synthesized and evaluated for their affinity toward human histamine H1 receptor and Caco-2 cell permeability. Selected compounds were further evaluated for their oral anti-histaminic activity in mice and bioavailability in rats. Finally, promising compounds were examined for their anti-inflammatory potential in mice OVA-induced biphasic cutaneous reaction model. Among the compounds tested, phenothiazineacetic acid compound 27 showed both histamine H1-receptor antagonistic activity and anti-inflammatory activity in vivo model. 相似文献
17.
《Bioorganic & medicinal chemistry letters》2020,30(11):127126
In this work, further structural investigations on the 8-amino-2-phenyl-6-aryl-1,2,4-triazolo[4,3-a]pyrazin-3-one series were carried out to achieve potent and selective human A2A adenosine receptor (AR) antagonists. Different ether and amide moieties were attached at the para-position of the 6-phenyl ring, thus leading to compounds 1–9 and 10–18, respectively. Most of these moieties contained terminal basic rings (pyrrolidine, morpholine, piperidine and substituted piperazines) which were thought to confer good physicochemical and drug-like properties.Compounds 11–16, bearing the amide linker, possessed high affinity and selectivity for the hA2A AR (Ki = 3.6–11.8 nM). Also derivatives 1–9, featuring an ether linker, preferentially targeted the hA2A AR but with lower affinity, compared to those of the relative amide compounds. Docking studies, carried out at the hA2A AR binding site, highlighted some crucial ligand-receptor interactions, particularly those provided by the appended substituent whose nature deeply affected hA2A AR affinity. 相似文献
18.
Kristoffer Sahlholm Johanna Nilsson Daniel Marcellino Kjell Fuxe Peter Århem 《生物化学与生物物理学报:生物膜》2012,1818(12):3081-3089
Agonist potency at some neurotransmitter receptors has been shown to be regulated by voltage, a mechanism which has been suggested to play a crucial role in the regulation of neurotransmitter release by inhibitory autoreceptors. Likewise, receptor deactivation rates upon agonist removal have been implicated in autoreceptor function. Using G protein-coupled potassium (GIRK) channel activation in Xenopus oocytes as readout of receptor activity, we have investigated the voltage sensitivities and signaling kinetics of the hH3445 and hH3365 isoforms of the human histamine H3 receptor, which functions as an inhibitory auto- and heteroreceptor in the nervous system. We have also investigated both the human and the mouse homologues of the related histamine H4 receptor, which is expressed mainly on hematopoietic cells. We found that the hH3445 receptor is the most sensitive to voltage, whereas the hH3365 and H4 receptors are less affected. We further observed a marked difference in response deactivation kinetics between the hH3445 and hH3365 isoforms, with the hH3365 isoform being five to six-fold slower than the hH3445 receptor. Finally, using synthetic agonists, we found evidence for agonist-specific voltage sensitivity at the hH4 receptor. The differences in voltage sensitivities and deactivation kinetics between the hH3445, hH3365, and H4 receptors might be relevant to their respective physiological roles. 相似文献
19.
Ramakrishna V.S. Nirogi Rajeshkumar Badange Ramasastri Kambhampati Anil Chindhe Amol D. Deshpande Vinaykumar Tiriveedhi Vishwottam Kandikere Nageswararao Muddana Renny Abraham Mukkanti Khagga 《Bioorganic & medicinal chemistry letters》2012,22(24):7431-7435
4-(Piperazin-1-yl methyl)-N1-arylsulfonyl indole derivatives were designed and synthesized as 5-HT6 receptor (5-HT6R) ligands. The lead compound 6a, from this series shows potent in vitro binding affinity, good PK profile, no CYP liabilities and activity in animal models of cognition. 相似文献
20.
Shinya Harusawa Koichi Sawada Takuji Magata Hiroki Yoneyama Lisa Araki Yoshihide Usami Kouta Hatano Kouichi Yamamoto Daisuke Yamamoto Atsushi Yamatodani 《Bioorganic & medicinal chemistry letters》2013,23(23):6415-6420
S-Alkyl-N-alkylisothiourea compounds containing various cyclic amines were synthesized in the search for novel nonimidazole histamine H3 receptor (H3R) antagonists. Among them, four N-alkyl S-[3-(piperidin-1-yl)propyl]isothioureas 18, 19, 22, and 23 were found to exhibit potent and selective H3R antagonistic activities against in vitro human H3R, but were inactive against in vitro human H4R. Furthermore, three alkyl homologs 18–20 showed inactivity for histamine release in in vivo rat brain microdialysis, suggesting differences in antagonist affinities between species. In addition, in silico docking studies of N-[4-(4-chlorophenyl)butyl]-S-[3-piperidin-1-yl)propyl]isothiourea 19 and a shorter homolog 17 with human/rat H3Rs revealed that structural differences between the antagonist-docking cavities of rat and human H3Rs were likely caused by the Ala122/Val122 mutation. 相似文献