共查询到20条相似文献,搜索用时 15 毫秒
1.
Röver S Adams DR Bénardeau A Bentley JM Bickerdike MJ Bourson A Cliffe IA Coassolo P Davidson JE Dourish CT Hebeisen P Kennett GA Knight AR Malcolm CS Mattei P Misra A Mizrahi J Muller M Porter RH Richter H Taylor S Vickers SP 《Bioorganic & medicinal chemistry letters》2005,15(15):3604-3608
Synthesis and evaluation of the activity of new 4-methyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles as 5-HT(2C) receptor agonists are described. Appropriately substituted, several analogs displayed selectivity against the other 5-HT(2) receptor subtypes of 1 order of magnitude or more. Selectivity was improved for several compounds versus the lead 1, increasing the therapeutic interest in this series of 5-HT(2C) receptor agonists. 相似文献
2.
Tye H Mueller SG Prestle J Scheuerer S Schindler M Nosse B Prevost N Brown CJ Heifetz A Moeller C Pedret-Dunn A Whittaker M 《Bioorganic & medicinal chemistry letters》2011,21(1):34-37
The discovery of a novel series of 5-HT2C agonists based on a tricyclic pyrazolopyrimidine scaffold is described. Compounds with good levels of in vitro potency and moderate to good levels of selectivity with respect to the 5-HT2A and 5-HT2B receptors were identified. One of the analogues (7g) was found to be efficacious in a sub-chronic weight loss model. A key limitation of the series of compounds was that they were found to be potent inhibitors of the hERG ion channel. Some compounds, bearing polar side chains were identified which showed a much reduced hERG liability however these compounds were sub-optimal in terms of their in vitro potency or selectivity. 相似文献
3.
Pascal Y Andrianjara CR Auclair E Avenel N Bertin B Calvet A Féru F Lardon S Moodley I Ouagued M Payne A Pruniaux MP Szilagyi C 《Bioorganic & medicinal chemistry letters》2000,10(1):35-38
A novel series of benzodiazepine derivatives have been discovered as inhibitors of PDE4 enzymes. We have found that our compounds are selective versus other PDE enzymes, and that the activity can be modulated by specific structural modifications. One compound exhibited a strong eosinophilic infiltration inhibiting action on sensitized Brown-Norway rats (compound 9, 5.1 mg/kg p.o.), moreover this compound is not emetic at 3 mg/kg i.v. 相似文献
4.
Alexandre V. Ivachtchenko Eugen B. Frolov Oleg D. Mitkin Sergei E. Tkachenko Ilya M. Okun Alex V. Khvat 《Bioorganic & medicinal chemistry letters》2010,20(1):78-82
Syntheses, biological evaluation, and structure–activity relationships for a series of novel 5-styryl and 5-phenethyl analogs of dimebolin are disclosed. The novel derivatives and dimebolin share a broad spectrum of activities against therapeutically relevant targets. Among all synthesized derivatives, 2,8-dimethyl-5-[(Z)-2-phenylvinyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and its 5-phenethyl analog are the most potent blockers of 5-HT7, 5-HT6, 5-HT2C, Adrenergic α2 and H1 receptors. The general affinity rank order towards the studied receptors was Z-3(2) > 4(2) ? 4(3) ? dimebolin, all of them having highest affinities to 5-HT7 receptors. 相似文献
5.
N. Krogsgaard-Larsen A.A. Jensen J. Kehler 《Bioorganic & medicinal chemistry letters》2010,20(18):5431-5433
Novel 7-phenylsulfanyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indoles are synthesized using a six-step protocol. Notably, the synthesis route make use of a new and improved ring-closing methodology for the assembly of the hexahydro-pyrazino[1,2-a]indole scaffold, which is based on intramolecular C–H insertion of a carbene. The compounds act as dual serotonin 5-HT2C- and 5-HT6-ligands. 相似文献
6.
Sabb AL Vogel RL Welmaker GS Sabalski JE Coupet J Dunlop J Rosenzweig-Lipson S Harrison B 《Bioorganic & medicinal chemistry letters》2004,14(10):2603-2607
Evaluation of selected compounds from our Corporate Compound Library in a human 5-HT(2C) receptor binding assay led to the discovery of WAY-629, a cyclohexyl[b][1,4]benzodiazepinoindole (K(i) 56 nM, E(max) 90%), which is selective for the 5-HT(2C) receptor versus other serotonin receptor subtypes, and dopamine, histamine, adrenergic, and muscarinic receptors. In addition, WAY-629 was active in vivo in a rat model of feeding behavior. An SAR study based on WAY-629 led to compound 11 (K(i) 13 nM, E(max) 102%). 相似文献
7.
John M. Fevig Jianxin Feng Karen A. Rossi Keith J. Miller Ginger Wu Chen-Pin Hung Thao Ung Sarah E. Malmstrom Ge Zhang William J. Keim Mary Jane Cullen Kenneth W. Rohrbach Qinling Qu Jinping Gan Mary Ann Pelleymounter Jeffrey A. Robl 《Bioorganic & medicinal chemistry letters》2013,23(1):330-335
A series of 2,3,3a,4-tetrahydro-1H-pyrrolo[3,4-c]isoquinolin-5(9bH)-ones is described, several examples of which exhibit potent 5-HT2C agonism with excellent selectivity over the closely related 5-HT2A and 5-HT2B receptors. Compounds such as 38 and 44 were shown to be effective in reducing food intake in an acute rat feeding model. 相似文献
8.
Breslin HJ Kukla MJ Kromis T Cullis H De Knaep F Pauwels R Andries K De Clercq E Janssen MA Janssen PA 《Bioorganic & medicinal chemistry》1999,7(11):2427-2436
4,5,6,7-Tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1 H)-ones (TIBO), 1, have been shown to significantly inhibit HIV-1 replication, as reported in detail in our prior publications. Since our earlier reports, we have modified the TIBO structures 1 by removing the 5-membered ring of 1, generating 1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-ones (TBO), 4, a bicyclic series of compounds. Although compounds 4 possess modest activity when compared to TIBO analogues 1, they clearly demonstrated significant anti-HIV-1 activity. 相似文献
9.
Richter HG Adams DR Benardeau A Bickerdike MJ Bentley JM Blench TJ Cliffe IA Dourish C Hebeisen P Kennett GA Knight AR Malcolm CS Mattei P Misra A Mizrahi J Monck NJ Plancher JM Roever S Roffey JR Taylor S Vickers SP 《Bioorganic & medicinal chemistry letters》2006,16(5):1207-1211
Further lead optimization efforts on previously described 1,2,3,4,10,10a-hexahydro-1H-pyrazino[1,2-a]indoles led to the new class of 5,5a,6,7,8,9-hexahydro-pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazines culminating in the discovery of (5aR,9R)-2-[(cyclopropylmethoxy)methyl]-5,5a,6,7,8,9-hexahydro-9-methyl-pyrido[3', 2':4,5]pyrrolo[1,2-a]pyrazine 18 as a potent, full 5-HT(2C) receptor agonist with an outstanding selectivity profile and excellent hERG and phospholipidosis properties. 相似文献
10.
Spasov A. A. Zhukovskaya O. N. Maltsev D. V. Miroshnikov M. V. Skripka M. O. Sultanova K. T. Morkovnik A. S. 《Russian Journal of Bioorganic Chemistry》2020,46(1):107-114
Russian Journal of Bioorganic Chemistry - This paper presents a study of the anxiolytic activity of compounds that belong to two classes of chemical groups: derivatives of... 相似文献
11.
Annedi SC Ramnauth J Cossette M Maddaford SP Dove P Rakhit S Andrews JS Porreca F 《Bioorganic & medicinal chemistry letters》2012,22(7):2510-2513
A novel class of 1,7-disubstituted 2,3,4,5-tetrahydro-1H-benzo[b]azepine derivatives was designed, synthesized and evaluated as human nitric oxide synthase (NOS) inhibitors. Structure-activity relationship studies based on various basic amine side chains attached at the 1-position of the 2,3,4,5-tetrahydro-1H-benzo[b]azepine ring led to the identification of several potent and highly selective inhibitors (17, 18, 25, (±)-39, and (±)-40) of human neuronal NOS. The potential therapeutic application of one of these new selective nNOS inhibitors (17) was demonstrated in an in vivo spinal nerve ligation model of neuropathic pain, and various in vitro safety pharmacology studies such as the hERG K(+) channel inhibition assay and high throughput broad screen (minimal activity at 79 receptors/transporters/ion channels). 相似文献
12.
Bentley JM Adams DR Bebbington D Benwell KR Bickerdike MJ Davidson JE Dawson CE Dourish CT Duncton MA Gaur S George AR Giles PR Hamlyn RJ Kennett GA Knight AR Malcolm CS Mansell HL Misra A Monck NJ Pratt RM Quirk K Roffey JR Vickers SP Cliffe IA 《Bioorganic & medicinal chemistry letters》2004,14(9):2367-2370
A series of 1-(1-indolinyl)-2-propylamines was synthesised and evaluated as 5-HT(2C) receptor agonists for the treatment of obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and radioligand binding data for all of the compounds at 5-HT(2) receptor subtypes are reported. A number of compounds were found to reduce food intake in rats after oral administration. 相似文献
13.
Bromidge SM Davies S Duckworth DM Forbes IT Jones GE Jones J King FD Blackburn TP Holland V Kennett GA Lightowler S Middlemiss DN Riley GJ Trail B Wood MD 《Bioorganic & medicinal chemistry letters》2000,10(16):1867-1870
Bisarylmethoxyethers have been identified with nanomolar 5-HT2C affinity and selectivity over both 5-HT2A and 5-HT2B receptors. Compounds such as 1, 2, 8, 12, 14 and 18 have potent oral activity in a centrally mediated pharmacodynamic model of 5-HT2C function and their therapeutic potential is currently under further investigation. 相似文献
14.
Bromidge SM Bertani B Borriello M Faedo S Gordon LJ Granci E Hill M Marshall HR Stasi LP Zucchelli V Merlo G Vesentini A Watson JM Zonzini L 《Bioorganic & medicinal chemistry letters》2008,18(20):5653-5656
Investigation of a series 6-[2-(4-aryl-1-piperazinyl)ethyl]-2H-1,4-benzoxazin-3(4H)-ones has led to the discovery of potent 5-HT(1A/1B/1D) receptor antagonists with and without additional SerT affinity. Modulation of the different target activities gave compounds with a range of profiles suitable for further in vivo characterization. 相似文献
15.
K Kondo H Ogawa H Yamashita H Miyamoto M Tanaka K Nakaya K Kitano Y Yamamura S Nakamura T Onogawa T Mori M Tominaga 《Bioorganic & medicinal chemistry》1999,7(8):1743-1754
We previously reported a series of benzazepine derivatives as orally active nonpeptide arginine vasopressin (AVP) V2 receptor antagonists. After the lead structure OPC-31260 was structurally evaluated and optimized, the introduction of the 7-Cl moiety on the benzazepine and 2-CH3 on the aminobenzoyl moiety enhanced its oral activity. The new AVP-V2 selective antagonist OPC-41061 was determined to be a potent and orally active agent. 相似文献
16.
Huck BR Llamas L Robarge MJ Dent TC Song J Hodnick WF Crumrine C Stricker-Krongrad A Harrington J Brunden KR Bennani YL 《Bioorganic & medicinal chemistry letters》2006,16(11):2891-2894
The 5-HT2C receptor has been implicated in the regulation of appetite. As such, small molecule agonists to this receptor may serve as novel therapies to combat obesity. We describe here the identification, synthesis, and SAR of a 5-HT2C agonist from a unique pyrimidine-diazabicyclo[3.3.0]octane series. This compound displayed good potency at the 5-HT2C receptor, modest selectivity relative to other 5-HT2 receptors, and was efficacious in an acute feeding study in rats. 相似文献
17.
Welmaker GS Nelson JA Sabalski JE Sabb AL Potoski JR Graziano D Kagan M Coupet J Dunlop J Mazandarani H Rosenzweig-Lipson S Sukoff S Zhang Y 《Bioorganic & medicinal chemistry letters》2000,10(17):1991-1994
A series of 2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5-(6H)ones and 2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxalines was shown to exhibit 5-HT2C agonist binding and functional activity. Compound 21R inhibited food intake over 2 h in fasted, male Sprague Dawley rats with ED50 values of 2 mg/kg (i.p.) and 10 mg/kg (p.o.). 相似文献
18.
Adams DR Bentley JM Benwell KR Bickerdike MJ Bodkin CD Cliffe IA Dourish CT George AR Kennett GA Knight AR Malcolm CS Mansell HL Misra A Quirk K Roffey JR Vickers SP 《Bioorganic & medicinal chemistry letters》2006,16(3):677-680
A series of 1-(1-pyrrolo(iso)quinolinyl)-2-propylamines was synthesised and evaluated as 5-HT(2C) receptor agonists for the treatment of obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and radioligand binding data for the compounds at 5-HT(2) receptor subtypes are reported. The analogue which showed the highest 5-HT(2C) binding affinity (27, 1.6nM) was found to be successful in reducing food intake in rats. 相似文献
19.
Tsukamoto I Koshio H Akamatsu S Kuramochi T Saitoh C Yatsu T Yanai-Inamura H Kitada C Yamamoto E Sakamoto S Tsukamoto S 《Bioorganic & medicinal chemistry》2008,16(21):9524-9535
The present work describes the discovery of novel series of (4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene)acetamide derivatives as arginine vasopressin (AVP) V(2) receptor agonists. By replacing the amide juncture in YM-35278 with a direct ring connection gave compound 10a, which acts as a V(2) receptor agonist. These studies provided the potent, orally active non-peptidic V(2) receptor agonists 10a and 10j. 相似文献
20.
Two series of N-(1-oxo-1,2,4,5-tetrahydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamides bearing piperazine and 1,4-diazepane moieties were synthesized and screened for their positive inotropic activity by measuring left atrium stroke volume on isolated rabbit heart preparations. Most of the derivatives exhibited better in vitro positive inotropic activity than the existing drug, milrinone, among which 2-(4-(4-chlorobenzyl)-1,4-diazepan-1-yl)-N-(1-oxo-1,2,4,5-tetrahydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamide 6c proved to be the most potent with 15.48 ± 0.27% increased stroke volume (milrinone: 2.46 ± 0.07%) at a concentration of 3 × 10(-5) M. The chronotropic effects of the compounds that exhibited inotropic effects were also evaluated. 相似文献