共查询到20条相似文献,搜索用时 31 毫秒
1.
Mahaney PE Vu AT McComas CC Zhang P Nogle LM Watts WL Sarkahian A Leventhal L Sullivan NR Uveges AJ Trybulski EJ 《Bioorganic & medicinal chemistry》2006,14(24):8455-8466
Compounds with a combination of norepinephrine and serotonin reuptake inhibition have been approved in the US and Europe for a number of indications, including major depressive disorder and pain disorders such as diabetic neuropathy and fibromyalgia. Efforts to design selective norepinephrine reuptake inhibitors based on SAR from the aryloxypropanamine series of monoamine reuptake inhibitors have led to the identification of a potent new class of dual acting norepinephrine and serotonin reuptake inhibitors, namely the 3-(1H-indol-1-yl)-3-arylpropan-1-amines. 相似文献
2.
Fish PV Deur C Gan X Greene K Hoople D Mackenny M Para KS Reeves K Ryckmans T Stiff C Stobie A Wakenhut F Whitlock GA 《Bioorganic & medicinal chemistry letters》2008,18(8):2562-2566
Single enantiomer (SS) and (RR) 2-[(phenoxy)(phenyl)methyl]morpholine derivatives 5, 8-23 are inhibitors of monoamine reuptake. Target compounds were prepared using an enantioselective synthesis employing a highly specific enzyme-catalysed resolution of racemic n-butyl 4-benzylmorpholine-2-carboxylate (26) as the key step. Structure-activity relationships established that serotonin and noradrenaline reuptake inhibition are functions of stereochemistry and aryl/aryloxy ring substitution. Consequently, selective SRI, selective NRI and dual SNRIs were all identified. One of these compounds, a potent and selective dual SNRI, (SS)-5a was selected as a candidate for further pre-clinical evaluation. 相似文献
3.
Previous studies showed that the dual serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE) reuptake inhibitor, duloxetine, increases bladder capacity and urethral sphincter electromyographic (EMG) activity in a cat model of acetic acid-induced bladder irritation. The present study aimed to determine the relative importance of 5-HT versus NE reuptake inhibition for mediating these effects by examining drugs that are selective for either the 5-HT or NE system or both. Similar to duloxetine, venlafaxine (0.1 to 10 mg/kg), also a dual serotonin and norepinephrine reuptake inhibitor, produced marked increases in bladder capacity and EMG activity that were reversed by methiothepin (0.3 mg/kg). S-norfluoxetine (0.01 to 10 mg/kg), a serotonin selective reuptake inhibitor, produced small but significant increases in bladder capacity and EMG activity at doses of 3 and 10 mg/kg. Thionisoxetine (0.01 to 3.0 mg/kg), a NE selective reuptake inhibitor, produced no effects on bladder capacity or sphincter EMG activity. Surprisingly, co-administration of thionisoxetine and s-norfluoxetine up to doses of 1 mg/kg of each compound produced no effect on lower urinary tract function. These doses were the maximum that could be administered in combination due to drug-induced emergence of skeletal muscle activity in chloralose-anesthetized animals. These results indicate that there are unexplained pharmacological differences between the effects of single compounds that exhibit dual NE and 5-HT reuptake inhibition and a combination of compounds that exhibit selective NE and 5-HT reuptake inhibition on lower urinary tract function. 相似文献
4.
Cases-Thomas MJ Masters JJ Walter MW Campbell G Haughton L Gallagher PT Dobson DR Mancuso V Bonnier B Giard T Defrance T Vanmarsenille M Ledgard A White C Ouwerkerk-Mahadevan S Brunelle FJ Dezutter NA Herbots CA Lienard JY Findlay J Hayhurst L Boot J Thompson LK Hemrick-Luecke S 《Bioorganic & medicinal chemistry letters》2006,16(7):2022-2025
A novel series of tertiary alcohol containing 2-substituted benzyl morpholines have been discovered as potent and selective inhibitors of the norepinephrine transporter. Efficient synthetic routes were developed featuring a highly diastereoselective nucleophilic addition of benzyl Grignard reagents to enantiopure (4-benzylmorpholin-2-yl)phenylmethanone (11) as the key synthetic step. In vitro binding affinity for the norepinephrine, dopamine and serotonin transporters and in vivo examination of a select compound (16) in a pharmacodynamic animal model for norepinephrine reuptake inhibition are presented. 相似文献
5.
Compounds possessing more than one functional activity incorporated into the same molecule may have advantages in treating complex disease states. Balanced serotonin/norepinephrine reuptake inhibitors (SNRIs) (i.e., (R)- and (S)-norduloxetine) were chemically linked to a PDE4 inhibitor via a five carbon bridge. The new dual SNRI/PDE4 inhibitors (i.e., (R)-15 and (S)-15) showed moderately potent serotonin reuptake inhibition (IC50 values of 442 and 404 nM, respectively) but low reuptake inhibition of norepinephrine (IC50 values of 2097 and 2190 nM, respectively) in vitro. The dual SNRI/PDE4 inhibitors (i.e., (R)-15 and (S)-15) also inhibited PDE4D2 (i.e., Ki values of 23 and 45 nM, respectively). Due to their synergistic functional activity, SNRI/PDE4 inhibitors may be effective in treating diseases such as depression. 相似文献
6.
《Bioorganic & medicinal chemistry》2016,24(21):5546-5555
In the search for potent dual norepinephrine and dopamine reuptake inhibitors, several substituted arylpiperazine–tetrazoles were designed, synthesized and evaluated for their neurotransmitter reuptake inhibitory activities. Various derivatives exhibited selective and strong neurotransmitter reuptake inhibitory activity. In particular, compounds with a three-carbon linker displayed selective and stronger potency than those with two-carbon and four-carbon linkers. Interestingly, six compounds, 9b, 9c, 9d, 9o, 9q and 9u displayed more effective activity than the standard drug, bupropion. The provided SAR data and potent biological activity can offer useful guidelines for designing dual norepinephrine and dopamine reuptake inhibitors as effective therapeutic agents for treatment of several central nervous system diseases. 相似文献
7.
A variety of tropane derivatives 14a–g were prepared via the reaction of the alcohol analogs 12a and 12b with substituted fluorobenzenes 13a–f. The prepared compounds were tested for their activity and selectivity toward the norepinephrine transporter (NET) and serotonin transporter (SERT) using yohimbine-induced mortality and 5-hydroxytryptophan-induced neurotoxicity in mice, respectively. All the tested compounds were found to be NE and 5-HT reuptake inhibitors except 14d which exhibited selective 5-HT reuptake inhibition activity. 相似文献
8.
As part of a discovery effort aimed at identifying novel norepinephrine reuptake inhibitors (NRIs), a number of substituted morpholines were designed and synthesized. The target compounds contain vicinal stereogenic centers, and the program was greatly facilitated by the adoption of efficient synthetic routes which allowed for the late stage incorporation of structural and physicochemical diversity into the targets. Structure-activity relationships were developed by optimizing individual ring components of the structure for NRI potency and for selectivity against other monoamine reuptake transporters. Several novel morpholine derivatives with a potent and selective NRI profile are described. 相似文献
9.
Boot JR Brace G Delatour CL Dezutter N Fairhurst J Findlay J Gallagher PT Hoes I Mahadevan S Mitchell SN Rathmell RE Richards SJ Simmonds RG Wallace L Whatton MA 《Bioorganic & medicinal chemistry letters》2004,14(21):5395-5399
A series of benzothienyloxy propylamines have been prepared and are demonstrated to be inhibitors of both serotonin and norepinephrine reuptake. 相似文献
10.
Suresh Paudel Xiao Min Srijan Acharya Daulat Bikram Khadka Goon Yoon Kyeong-Man Kim Seung Hoon Cheon 《Bioorganic & medicinal chemistry》2018,26(20):5538-5546
Two series of 4-arylpiperazine- and 4-benzylpiperidine naphthyl ethers were designed based on structure-activity relationship (SAR) and docking model of reported monoamine neurotransmitters reuptake inhibitors. The compounds were synthesized in 3-simple steps and their biological activities were evaluated. Several compounds were proven to be potent inhibitors of serotonin and norepinephrine reuptake. Computer docking was performed to study the interaction of the most potent compound 35 with human serotonin transporter. The results of the analyses suggest that 4-arylpiperazine- and 4-benzylpiperidine naphthyl ethers might be promising antidepressants worthy of further studies. 相似文献
11.
Beadle CD Boot J Camp NP Dezutter N Findlay J Hayhurst L Masters JJ Penariol R Walter MW 《Bioorganic & medicinal chemistry letters》2005,15(20):4432-4437
A novel series of 1-aryl-3,4-dihydro-1H-quinolin-2-ones have been discovered as potent and selective norepinephrine reuptake inhibitors. Efficient synthetic routes have been developed which allow for the multi-gram preparation of both final targets and advanced intermediates for SAR expansion. 相似文献
12.
David L. Gray Wenjian Xu Brian M. Campbell Amy B. Dounay Nancy Barta Susan Boroski Lynne Denny Lori Evans Nancy Stratman Al Probert 《Bioorganic & medicinal chemistry letters》2009,19(23):6604-6607
Compounds that are both norepinephrine reuptake inhibitors (NRI) and 5-HT1A partial agonists may have the potential to treat neuropsychiatric disorders including attention deficit hyperactivity disorder (ADHD) and depression. Targeted screening of NRI-active compounds for binding to the 5-HT1A receptor provided a series of thiomorpholinone hits with this dual activity profile. Several iterations of design, synthesis, and testing led to substituted piperidine diphenyl ethers which are potent NRIs with 5-HT1A partial agonist properties. In addition, optimization of these molecules provided compounds which exhibit selectivity for NRI over the dopamine (DAT) and serotonin (SERT) reuptake transporters. Monoamine and 5-HT1A in vitro functional activities for select compounds from the developed piperidine diphenyl ether series are also presented. 相似文献
13.
Pontillo J Wu D Ching B Hudson S Genicot MJ Gao Y Ewing T Fleck BA Gogas K Aparicio A Wang H Wen J Wade WS 《Bioorganic & medicinal chemistry letters》2008,18(23):6151-6155
The design synthesis and SAR of a series of chiral ring-constrained norepinephrine reuptake inhibitors with improved physicochemical properties is described. Typical compounds are potent (IC(50)s<10 nM), selective against the other monoamine transporters, weak CYP2D6 inhibitors (IC(50)s>1 microM) and stable to oxidation by human liver microsomes. In addition, the compounds exhibit a favorable polarity profile. 相似文献
14.
Boot JR Boulet SL Clark BP Cases-Thomas MJ Delhaye L Diker K Fairhurst J Findlay J Gallagher PT Gilmore J Harris JR Masters JJ Mitchell SN Naik M Simmonds RG Smith SM Richards SJ Timms GH Whatton MA Wolfe CN Wood VA 《Bioorganic & medicinal chemistry letters》2006,16(10):2714-2718
A series of N-alkyl-N-arylmethylpiperidin-4-amines have been prepared and are demonstrated to be inhibitors of both serotonin and norepinephrine reuptake. 相似文献
15.
Zhou J Kläss T Zhang A Johnson KM Wang CZ Ye Y Kozikowski AP 《Bioorganic & medicinal chemistry letters》2003,13(20):3565-3569
To further explore the structure-activity relationships (SARs) of certain tropanes, and to gain insights into the structural features required for high activity and selectivity at norepinephrine transporters (NET), we have introduced both five- and six-membered heteroaromatic moieties such as substituted pyridyl, pyrazinyl, pyrimidyl, thiazolyl, and mono- or disubstituted thienyl groups into conformationally constrained, tricyclic tropane analogues. A number of (Z)-9-(heteroarylmethylene)-7-azatricyclo[4.3.1.0(3,7)]decanes were synthesized, and their abilities to block dopamine, serotonin, and norepinephrine reuptake by their respective transporters were evaluated. It was found that the five- or six-membered N-containing aromatics are too basic to display high NET activity, while some of the thiophene analogues were identified as potent and selective NET inhibitors. 相似文献
16.
An T. Vu Stephen T. Cohn Eugene A. Terefenko William J. Moore Puwen Zhang Paige E. Mahaney Eugene J. Trybulski Igor Goljer Rebecca Dooley Jenifer A. Bray Grace H. Johnston Jennifer Leiter Darlene C. Deecher 《Bioorganic & medicinal chemistry letters》2009,19(9):2464-2467
A series of 3-(arylamino)-3-phenylpropan-2-olamines was prepared and screened for their ability to inhibit monoamine reuptake. A number of analogues displayed significant dual norepinephrine and serotonin reuptake inhibition. Compounds in this class exhibited minimal affinity for the dopamine transporter. 相似文献
17.
Bymaster FP Beedle EE Findlay J Gallagher PT Krushinski JH Mitchell S Robertson DW Thompson DC Wallace L Wong DT 《Bioorganic & medicinal chemistry letters》2003,13(24):4477-4480
A series of naphthalenyloxy-arylpropylamines have been prepared and are demonstrated to be inhibitors of both serotonin and norepinephrine reuptake. One member of this series, duloxetine (Cymbalta™) has proven to be effective in clinical trials for the treatment of depression. 相似文献
18.
Andrew Fensome Joel Goldberg Casey C. McComas Eugene J. Trybulski Richard P. Woodworth Darlene C. Deecher Garth T. Whiteside Puwen Zhang 《Bioorganic & medicinal chemistry letters》2010,20(5):1555-1558
Two related series of selective norepinephrine reuptake inhibitors were synthesized based on 3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide or 3,4-dihydrosulfostyril cores, and screened for monoamine reuptake inhibition. Structure–activity relationships were determined for the series’ in vitro potency and selectivity versus serotonin or dopamine transporter inhibition, and analogs based on both cores were identified as potent and selective NRIs. The 3,4-dihydrosulfostyril series was further tested for microsome stability, and compound 16j, which was optimized for both potency and stability, showed efficacy in an in vivo model of thermoregulatory dysfunction. 相似文献
19.
McComas CC Vu AT Mahaney PE Cohn ST Fensome A Marella MA Nogle L Trybulski EJ Ye F Zhang P Alfinito P Bray J Johnston G Koury E Deecher DC 《Bioorganic & medicinal chemistry letters》2008,18(18):4929-4931
Norepinephrine and serotonin play an important role in a wide variety of biological processes and are implicated in a number of neurological disorders. A novel class of 1-(3-amino-1-phenylpropyl)indolin-2-ones was designed and synthesized that displays potent norepinephrine reuptake inhibition while maintaining high selectivity (>100-fold) against the human serotonin and dopamine transporters. 相似文献
20.
Takeuchi K Kohn TJ Honigschmidt NA Rocco VP Spinazze PG Koch DJ Nelson DL Wainscott DB Ahmad LJ Shaw J Threlkeld PG Wong DT 《Bioorganic & medicinal chemistry letters》2003,13(11):1903-1905
A series of 1-aryloxy-3-piperidinylpropan-2-ols possessing potent dual 5-HT(1A) receptor antagonism and serotonin reuptake inhibition was discovered. 1-(1H-Indol-4-yloxy)-3-(4-benzo[b]thiophen-2-ylpiperidinyl)propan-2-ols exhibited selective and high affinity at the 5-HT(1A) receptor and serotonin reuptake inhibition at nanomolar concentrations for dual activities. 相似文献