共查询到20条相似文献,搜索用时 0 毫秒
1.
Trani G Baddeley SM Briggs MA Chuang TT Deeks NJ Johnson CN Khazragi AA Mead TL Medhurst AD Milner PH Quinn LP Ray AM Rivers DA Stean TO Stemp G Trail BK Witty DR 《Bioorganic & medicinal chemistry letters》2008,18(20):5698-5700
Starting from a benzazepine sulfonamide 5-HT(6) receptor antagonist lead with limited brain penetration, application of a strategy of conformational constraint and reduction of hydrogen bond donor count led to a novel series of tricyclic derivatives with high 5-HT(6) receptor affinity and excellent brain:blood ratios. 相似文献
2.
Bromidge SM Clarke SE King FD Lovell PJ Newman H Riley G Routledge C Serafinowska HT Smith DR Thomas DR 《Bioorganic & medicinal chemistry letters》2002,12(10):1357-1360
The synthesis of novel 3-(octahydropyrido[1,2-a]pyrazin-2-yl)- and 3-(hexahydropyrrolo[1,2-a]pyrazin-2-yl)phenyl-2-benzo[b]thiophene sulphonamide derivatives 3, (S)-4 and (R)-4 is described. The compounds show high affinity for the 5-HT6 receptor, excellent selectivity against a range of other receptors and good brain penetration. 相似文献
3.
Hervé Geneste Swati Bhowmik Marcel M. van Gaalen Wilfried Hornberger Charles W. Hutchins Astrid Netz Thorsten Oost Liliane Unger 《Bioorganic & medicinal chemistry letters》2018,28(19):3260-3264
Herein we report the discovery of a novel oxindole-based series of vasopressin 1b (V1b) receptor antagonists. Introducing a substituted piperazine moiety and optimizing the southern and the northern aromatic rings resulted in potent, selective and brain penetrant V1b receptor antagonists. Compound 9c was found to be efficacious in a rat model of anti-depressant activity (3?mg/kg, ip). Interestingly, both moderate terminal half-life and moderate bioavailability could be achieved despite sub-optimal microsomal stability. 相似文献
4.
Cole DC Lennox WJ Stock JR Ellingboe JW Mazandarani H Smith DL Zhang G Tawa GJ Schechter LE 《Bioorganic & medicinal chemistry letters》2005,15(21):4780-4785
Several series of conformationally constrained N1-arylsulfonyltryptamine derivatives were prepared and tested for 5-HT6 receptor binding affinity and ability to modulate cAMP production in a cyclase assay. The 3-piperidin-3-yl-, 3-(1-methylpyrrolidin-2-ylmethyl)-, and 3-pyrrolidin-3-yl-1H-indole arrays (8-13) appear to be able to adopt a conformation that allows high affinity 5-HT6 receptor binding, while the beta-carboline array 14 binds with a significantly weaker (10- to 100-fold) affinity. N1-Benzenesulfonyl-3-piperidin-3-yl-1H-indole 9a is a high affinity full agonist with EC50 = 24 nM. Several of the N1-arylsulfonyl-3-(1-methylpyrrolidin-2-ylmethyl)-1H-indole derivatives behave as very potent antagonists ((S)-11r, (S)-11t; IC50 = 0.8, 1.0 nM). 相似文献
5.
A novel series of arylsulfonylaminomethyl-3-(1-phenyl-5-isopropyl)pyrazoles was evaluated for serotonin receptor subtype 6 (5-HT6R) antagonistic effects in vitro. We also investigated their neuropathic pain-alleviating effects in vivo using a rat spinal nerve ligation (SNL) model. Bicyclic aromatic sulfonamino groups, such as naphthalene and quinolin-substituted derivatives, showed good 5-HT6 inhibitory activity in vitro. Among them, selected compounds, 12 and 13, having 8-quinoylsulfonamino groups, showed potent neuropathic pain-alleviating effects in the rat model. 相似文献
6.
Isaac M Slassi A Xin T MacLean N Wilson J McCallum K Wang H Demchyshyn L 《Bioorganic & medicinal chemistry letters》2000,10(15):1719-1721
A novel series of 6-bicyclopiperazinyl-1-arylsulfonylindoles and 6-bicyclopiperidinyl-1-arylsulfonylindoles derivatives was synthesized and found to be potent and selective 5-HT6 receptor antagonists. 相似文献
7.
Bienaymé H Chêne L Grisoni S Grondin A Kaloun el-B Poigny S Rahali H Tam E 《Bioorganic & medicinal chemistry letters》2006,16(18):4830-4833
A functional screening highlighted a series of spiro-piperidines as 5-HT2B receptor antagonists. Preliminary structure-activity relationship has been explored driving to potent antagonists (IC50 = 1 nM) and indicating directions for further explorations. 相似文献
8.
Liu KG Robichaud AJ Greenfield AA Lo JR Grosanu C Mattes JF Cai Y Zhang GM Zhang JY Kowal DM Smith DL Di L Kerns EH Schechter LE Comery TA 《Bioorganic & medicinal chemistry》2011,19(1):650-662
As part of our efforts to develop agents for cognitive enhancement, we have been focused on the 5-HT6 receptor in order to identify potent and selective ligands for this purpose. Herein we report the identification of a novel series of 3-sulfonylindazole derivatives with acyclic amino side chains as potent and selective 5-HT6 antagonists. The synthesis and detailed SAR of this class of compounds are reported. 相似文献
9.
Forbes IT Cooper DG Dodds EK Douglas SE Gribble AD Ife RJ Lightfoot AP Meeson M Campbell LP Coleman T Riley GJ Thomas DR 《Bioorganic & medicinal chemistry letters》2003,13(6):1055-1058
Novel 5-HT(7) receptor antagonists containing the benzocycloheptanone core were identified from high throughput screening. Molecular modelling and SAR studies have converted these intractable hits into a more potent, selective and tractable series, exemplified by compound (25), SB-691673. 相似文献
10.
Yoon J Yoo EA Kim JY Pae AN Rhim H Park WK Kong JY Park Choo HY 《Bioorganic & medicinal chemistry》2008,16(10):5405-5412
Twenty-four compounds of 4-methoxy-N-[3-(4-substituted phenyl-piperazine-1-yl)propyl] benzene sulfonamides and N-[3-(4-substituted phenyl-piperazine-1-yl)propyl] naphthyl sulfonamides were prepared and evaluated as 5-HT(7) receptor antagonists. Most of the compounds showed the IC(50) values of 12-580nM. Four methyl branched analogues were also obtained, but the activity for methyl branched analogues was almost same as its straight chain congeners. Among the synthesized compounds, 3c showed a good activity on 5-HT(7) receptors and a good selectivity on 5-HT(1a), 5-HT(2a), 5-HT(2c), and 5-HT(6) receptors. 相似文献
11.
Byung-Hwan Lee Min Jung Choi Mi Na Jo Hee Jeong Seo Seung-Yeol Nah Yong Seo Cho Ghilsoo Nam Ae Nim Pae Hyewhon Rhim Hyunah Choo 《Bioorganic & medicinal chemistry》2009,17(13):4793-4796
5-HT3A receptor antagonists have been used mainly for the treatment of nausea and vomiting. These days, the antagonists are of special interest due to their therapeutic potential to treat other diseases such as depression, psychotic disorder, drug abuse, and irritable bowel syndrome. To discover novel 5-HT3A receptor antagonists, we screened our in-house small molecule library, resulting in identifying the quinazolindione derivatives as potent 5-HT3A receptor antagonists. For the purpose of structure–activity relationship study, 24 quinazolindione analogues were biologically evaluated against 5-HT3A receptor. Among those, KKHT10612 shows the best antagonistic effect against 5-HT3A receptor with an IC50 value of 0.8 μM which is comparable with that of the reference compound, MDL72222, and selectivity over T-type calcium channel as well. 相似文献
12.
Seong CM Park WK Park CM Kong JY Park NS 《Bioorganic & medicinal chemistry letters》2008,18(2):738-743
A 5,7-dichloro-3-phenyl-3-methyl-quinoline-2,4-dione (11a) has been identified in a random screen as a lead for 5-HT(6) antagonist. During the lead optimization process, several analogs were synthesized and their biological activities were investigated. Within this series, several compounds display high binding affinity and selectivity for the 5-HT(6) receptor. In particular, 3-(4-hydroxyphenyl)-3-methyl-quinoline-2,4-dione (12f) exhibits high affinity (K(i)=12.3 nM) for 5-HT(6) receptor with good selectivity over other serotonin and dopamine (D(1)-D(4)) receptor subtypes. In a functional adenylyl cyclase stimulation assay, this compound exhibited considerable antagonistic activity (IC(50)=0.61 microM). 相似文献
13.
Zhao SH Berger J Clark RD Sethofer SG Krauss NE Brothers JM Martin RS Misner DL Schwab D Alexandrova L 《Bioorganic & medicinal chemistry letters》2007,17(12):3504-3507
A series of novel 3,4-dihydro-2H-benzo[1,4]oxazine derivatives has been designed and synthesized as 5-HT(6) receptor antagonists. Many of the compounds displayed subnanomolar affinities for the 5-HT(6) receptor and good brain penetration in rats. The relationship of structure and lipophilicity to hERG inhibition of this series of compounds is discussed. 相似文献
14.
Ramakrishna V.S. Nirogi Anand V. Daulatabad G. Parandhama Shaikh Mohammad K.R. Sastri Anil K. Shinde P.K. Dubey 《Bioorganic & medicinal chemistry letters》2010,20(15):4440-4443
A series of novel aryl aminosulfonamides was designed and synthesized as 5-HT6 receptor ligands. Many compounds screened in a functional reporter gene based assay displayed potent antagonistic activity with Kb values in the range of 0.02–10 nM. The lead compound 11m exemplified in this series showed good ADME surrogate properties, acceptable pharmacokinetic profile and is active in animal models of cognition like novel object recognition test and Morris water maze. The compound was selected for detailed profiling. 相似文献
15.
Ladduwahetty T Boase AL Mitchinson A Quin C Patel S Chapman K MacLeod AM 《Bioorganic & medicinal chemistry letters》2006,16(12):3201-3204
Based on an existing series of 5-HT2A receptor ligands containing a basic nitrogen, we designed a non-basic lead that had reduced affinity for both the 5-HT2A receptor and the IKr potassium channel. The present paper describes the development of this lead to a novel series of non-basic piperidine sulfonamides and amides that have high affinity for the 5-HT2A receptor, whilst maintaining excellent selectivity over off target activities such as the IKr channel. This work has shown that the proposed pharmacophore model for the 5-HT2A receptor which suggests that a basic nitrogen is required for the binding of ligands is questionable. 相似文献
16.
Euna Yoo Juhee Yoon Ae Nim Pae Hyewhon Rhim Woo-Kyu Park Jae Yang Kong Hea-Young Park Choo 《Bioorganic & medicinal chemistry》2010,18(4):1665-1675
A novel series of 5-HT2A ligands that contain a (phenylpiperazinyl-propyl)arylsulfonamides skeleton was synthesized. Thirty-seven N-(cycloalkylmethyl)-4-methoxy-N-(3-(4-arylpiperazin-1-yl)propyl)-arylsulfonamide and N-(4-(4-arylpiperazin-1-yl)butan-2-yl)-arylsulfonamide compounds were obtained. The binding of these compounds to the 5-HT2A, 5-HT2C, and 5-HT7 receptors was evaluated. Most of the compounds showed IC50 values of less than 100 nM and exhibited high selectivity for the 5-HT2A receptor. Among the synthesized compounds, 16a and 16d showed good affinity at 5-HT2A (IC50 = 0.7 nM and 0.5 nM) and good selectivity over 5-HT2C (50–100 times) and 5-HT7 (1500–3000 times). 相似文献
17.
Indoloxypropanolamine analogues as 5-HT(1A) receptor antagonists 总被引:1,自引:0,他引:1
Krushinski JH Schaus JM Thompson DC Calligaro DO Nelson DL Luecke SH Wainscott DB Wong DT 《Bioorganic & medicinal chemistry letters》2007,17(20):5600-5604
Analogues of pindolol, 1-(1H-indol-4-yloxy)-3-isopropylamino-propan-2-ol, were synthesized and evaluated as 5-HT(1A) receptor antagonists. The structural features required for optimal binding to the 5-HT1A receptor are as follows: S-2-propanol linker, 4-indoloxy substituent, and a large lipophilic cyclic amine substituent. 相似文献
18.
Henderson AJ Guzzo PR Ghosh A Kaur J Koo JM Nacro K Panduga S Pathak R Shimpukade B Tan V Xiang K Wierschke JD Isherwood ML 《Bioorganic & medicinal chemistry letters》2012,22(4):1494-1498
A new series of epiminocyclohepta[b]indoles with potent 5-HT(6) antagonist activity were discovered and optimized using in vitro protocols. One compound from this series was progressed to advanced pharmacokinetic (PK) studies followed by 5-HT(6) receptor occupancy studies. The compound was found to have excellent oral absorption, a highly favorable PK profile and demonstrated pharmacodynamic interaction with the 5-HT(6) receptor as shown by ex vivo autoradiography. 相似文献
19.
Kevin G. Liu Jennifer R. Lo Thomas A. Comery Guo Ming Zhang Jean Y. Zhang Dianne M. Kowal Deborah L. Smith Li Di Edward H. Kerns Lee E. Schechter Albert J. Robichaud 《Bioorganic & medicinal chemistry letters》2009,19(9):2413-2415
As part of our continuing efforts to identify therapeutics for CNS diseases, such as schizophrenia and Alzheimer’s disease (AD), we have been focused on the 5-HT6 receptor in an attempt to identify ligands as a potential treatment for cognitive dysfunction. Herein we report the identification of a novel series of 1-sulfonylindazole derivatives as potent and selective 5-HT6 antagonists. The synthesis and SAR of this class of compounds are reported. Several potent compounds in both binding and cyclase functional assays also display good selectivity, microsomal stability, solubility, and brain penetration as well as low cytochrome P450 inhibition. One compound exemplified in this series showed 24% oral bioavailability and in vivo efficacy in a NOR cognition model at 10 mg/kg following an oral administration in rats. 相似文献
20.
André Alker Alfred Binggeli Andreas D. Christ Luke Green Hans Peter Maerki Rainer E. Martin Peter Mohr 《Bioorganic & medicinal chemistry letters》2010,20(15):4521-4525
Nicotinamides of benzyl-substituted 4-aminopiperidines and their seven-membered analogs of generic structure 2 and 2′ have been discovered as potent and selective SST5 antagonists. The activity (Ki) ranges from 2.4 to 436 nM. Most compounds exhibit decent physicochemical properties and follow a clear SAR pattern. Interestingly enough, the receptor is strongly enantiodiscriminating and binds in the amino-azepane-series only the (R)-enantiomer. 相似文献