共查询到20条相似文献,搜索用时 15 毫秒
1.
Todd A. Brugel Reed W. Smith Michael Balestra Christopher Becker Thalia Daniels Tiffany N. Hoerter Gerard M. Koether Scott R. Throner Laura M. Panko James J. Folmer Joseph Cacciola Angela M. Hunter Ruifeng Liu Philip D. Edwards Dean G. Brown John Gordon Norman C. Ledonne Mark Pietras Patricia Schroeder Linda A. Sygowski Matthew F. Peters 《Bioorganic & medicinal chemistry letters》2010,20(19):5847-5852
Initial high throughput screening efforts identified highly potent and selective kappa opioid receptor antagonist 3 (κ IC50 = 77 nM; μ:κ and δ:κ IC50 ratios >400) which lacked CNS exposure in vivo. Modification of this scaffold resulted in development of a series of 8-azabicyclo[3.2.1]octan-3-yloxy-benzamides showing potent and selectivity κ antagonism as well as good brain exposure. Analog 6c (κ IC50 = 20 nM; μ:κ = 36, δ:κ = 415) was also shown to reverse κ-agonist induced rat diuresis in vivo. 相似文献
2.
3D-QSAR models of Comparative of Molecular Field Analysis (CoMFA) and Comparative of Molecular Similarities Indices Analysis (CoMSIA) of 20 8-azabicyclo[3.2.1] octane (potent muscarinic receptor blocker) was performed. These benztropine analogs were optimized using ligand based alignment method. The conventional ligand-based 3D-QSAR studies were performed based on the low energy conformations employing database alignment rule. The ligand-based model gave q2 value 0.819 and 0.810 and r2 value 0.991 and 0.988 for CoMFA and CoMSIA, respectively, and the predictive ability of the model was validated. Results indicate that the CoMFA and CoMSIA models could be reliable model which may be used in the design of novel muscarinic antagonists as leads. 相似文献
3.
Napier S Wishart G Arbuckle W Baker J Barn D Bingham M Brown A Byford A Claxton C Craighead M Buchanan K Fielding L Gibson L Goodwin R Goutcher S Irving N MacSweeney C Milne R Mort C Presland J Sloan H Thomson F Turnbull Z Young T 《Bioorganic & medicinal chemistry letters》2011,21(10):3163-3167
The discovery of a novel series of 8-azabicyclo[3.2.1]octan-3-yl)-3-(4-chlorophenyl) propanamide antagonists of the vasopressin V1A receptor is disclosed. Compounds 47 and 48 were found to be high affinity, selective vasopressin V1A antagonists. 相似文献
4.
Huscroft IT Carlson EJ Chicchi GG Kurtz MM London C Raubo P Wheeldon A Kulagowski JJ 《Bioorganic & medicinal chemistry letters》2006,16(7):2008-2012
1-Phenyl-8-azabicyclo[3.2.1]octane ethers are NK(1) receptor antagonists. Substitution at the 6-exo-position led to high affinity NK(1) antagonists with a prolonged duration of action in vivo. Incorporation of an alpha-methyl substituent in the pendent benzyl ether side chain gave compounds with increased selectivity over the hERG channel. 相似文献
5.
Thomson CG Carlson E Chicchi GG Kulagowski JJ Kurtz MM Swain CJ Tsao KL Wheeldon A 《Bioorganic & medicinal chemistry letters》2006,16(4):811-814
A series of 8-azabicyclo[3.2.1]octane amine hNK1 antagonists has been investigated and structure-activity relationships of the benzylamine and 6-exo substituents described. Acidic substituents at C6 give a series of high affinity compounds for hNK1 with selectivity over the hERG channel. 相似文献
6.
Cocaine inhibits the dopamine transporter and the consequent elevation of dopamine is thought to contribute to the addictive properties of cocaine. Tropane analogues of cocaine, targeted to the dopamine transporter (DAT), are a significant focus of drug design for cocaine addiction medications. Herein, we report the function of the ortho hydroxy substituents in dopamine with respect to the azabicyclo[3.2.1]octane skeleton. The introduction of the o-dihydroxyl functionality led to reduced binding potency at monoamine transporters, rather than enhanced interaction with the DAT. It is therefore likely that the binding site for these compounds on the DAT is not the same as that for dopamine. Notwithstanding the moderate potency of the free catechols (>100 nM), 7 manifested stimulant activity with a duration of effect that exceeded 4 h in a rat locomotor activity assay. Compound 10, a diacetoxy prodrug for 7, substituted fully for cocaine in a rat drug-discrimination paradigm and is now undergoing further investigation as a potential medication for cocaine abuse. 相似文献
7.
Cheng J Izenwasser S Zhang C Zhang S Wade D Trudell ML 《Bioorganic & medicinal chemistry letters》2004,14(7):1775-1778
A series of epiboxidine homologues, 2- and 3-isoxazole substituted 8-azabicyclo[3.2.1]octane derivatives was synthesized and evaluated as potential ligands for neuronal nicotinic acetylcholine receptors in [(3)H]cytisine labeled rat brain. The 2beta-isoxazolyl-8-azabicyclo[3.2.1]octane 9b (K(i)=3 nM) was the most potent compound of the series with a binding affinity twice that of nicotine. The 3beta-isoxazolyl-8-azabicyclo[3.2.1]octane 15b (K(i)=148 nM) exhibited moderate affinity while the corresponding 2alpha- and 3alpha-isomers exhibited micromolar binding affinity. 相似文献
8.
Lainé DI Xie H Buffet N Foley JJ Buckley P Webb EF Widdowson KL Palovich MR Belmonte KE 《Bioorganic & medicinal chemistry letters》2007,17(22):6066-6069
In the course of our research program to develop novel muscarinic receptor antagonists for the treatment of COPD, new tropane carbamate derivatives were identified as potent anti-muscarinic agents. The synthesis, structure-activity relationships and pharmacological evaluation that led to the identification of compound 5o, are described. 相似文献
9.
A series of diarylmethoxymethyltropane-GBR hybrid analogues with all three possible stereochemical orientations at C3 were synthesized and evaluated at dopamine and serotonin transporters. The 3alpha derivatives were found to be the most potent compounds with the 3alpha-di(4-fluorophenyl)methoxymethyl-8-(3-phenylpropyl)-8-azabicyclo[3.2.1]octane 15b (Ki = 5 nM) being the most potent compound of the series. The corresponding 3-di(4-fluorophenyl)-methoxymethyl-8-(3-phenylpropyl)-8-azabicyclo[3.2.1]oct-2-ene 12b (Ki = 12 nM) was slightly less potent than the 3alpha-analogue, while the 3beta-di(4-fluorophenyl)methoxymethyl-8-(3-phenylpropyl)-8-azabicyclo[3.2.1]octane 23b (Ki = 78 nM) exhibited only modest affinity for the dopamine transporter. Only the 3alpha-analogue 15b (SERT/DAT = 48) exhibited higher SERT/DAT selectivity than GBR 12909. These results indicate that the dopamine transporter can tolerate some variability in proximity of the benzhydryl ether to the basic nitrogen atom of the tropane without loss in potency. In addition, the structure-activity data for these tropane-GBR 12909 hybrid analogues support previous findings that the stereochemical and conformational effects imparted by unsaturation at C3 are important for dopamine transporter selectivity over the serotonin transporter. 相似文献
10.
Jeroen C. Verheijen David J. Richard Kevin Curran Joshua Kaplan Ker Yu Arie Zask 《Bioorganic & medicinal chemistry letters》2010,20(8):2648-2653
Isosteric replacement of one of the 3,5-ethylene-bridged morpholines in 2-arylureidophenyl-4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)triazines led to significant improvements in human microsomal stability. 3-R-Me-morpholine and tetrahydropyran were identified as preferred isosteres for the bridged morpholine. Combination of tetrahydropyran substitution with an N-Me-piperazinophenylureido group led to 27, that selectively suppressed mTOR biomarkers in vivo and possessed excellent efficacy in a murine xenograft model. 相似文献
11.
Bradley AL Izenwasser S Wade D Cararas S Trudell ML 《Bioorganic & medicinal chemistry letters》2003,13(4):629-632
A series of 3-[2-(diarylmethoxyethylidene)]-8-alkylaryl-8-azabicyclo[3.2.1]octanes was synthesized and the binding affinities of the compounds were determined at the dopamine and serotonin transporters. The 8-phenylpropyl analogues 8a (K(i)=4.1 nM) and 8b (K(i)=3.7 nM) were the most potent compounds of the series with binding affinities 3 times greater than GBR-12909. In addition, 8a (SERT/DAT=327) was over 300-fold more selective for the dopamine transporter than the serotonin transporter. 相似文献
12.
Carson JR Coats SJ Codd EE Dax SL Lee J Martinez RP McKown LA Anne Neilson L Pitis PM Wu WN Zhang SP 《Bioorganic & medicinal chemistry letters》2004,14(9):2113-2116
The tertiary amide delta opioid agonist 2 is a potent antinociceptive agent. Compound 2 was metabolized in vitro and in vivo to secondary amide 3, a potent and selective micro opioid agonist. The SAR of a series of N-alkyl-4-[(8-azabicyclo[3.2.1]-oct-3-ylidene)phenylmethyl]benzamides was examined. 相似文献
13.
Rémy C. Lemoine Ann C. Petersen Lina Setti Thomas Baldinger Jutta Wanner Andreas Jekle Gabrielle Heilek André deRosier Changhua Ji David M. Rotstein 《Bioorganic & medicinal chemistry letters》2010,20(5):1674-1676
The bicyclic 5-amino-3-azabicyclo[3.3.0]octanes were shown to be effective replacements for the 3-amino-8-azabicyclo[3.2.1]octane found in the CCR5 antagonist maraviroc. 相似文献
14.
Lan Jiang David T. Beattie John R. Jacobsen Samuel Kintz Glenmar P. Obedencio Daisuke Saito Ioanna Stergiades Ross G. Vickery Daniel D. Long 《Bioorganic & medicinal chemistry letters》2017,27(13):2926-2930
Gastrointestinal dysfunction as a consequence of the use of opioid analgesics is of significant clinical concern. First generation drugs to treat these opioid-induced side-effects were limited by their negative impact on opioid receptor agonist-induced analgesia. Second generation therapies target a localized, peripherally-restricted, non-CNS penetrant drug distribution of opioid receptor antagonists. Herein we describe the discovery of the N-substituted-endo-3-(8-aza-bicyclo[3.2.1]oct-3-yl)-phenol and -phenyl carboxamide series of μ-opioid receptor antagonists. This report highlights the discovery of the key μ-opioid receptor antagonist pharmacophore and the optimization of in vitro metabolic stability through the application of a phenol bioisostere. The compounds 27a and 31a with the most attractive in vitro profile, formed the basis for the application of Theravance Biopharma’s multivalent approach to drug discovery to afford the clinical compound axelopran (TD-1211), targeted for the treatment of opioid-induced constipation. 相似文献
15.
Carson JR Coats SJ Codd EE Dax SL Lee J Martinez RP Neilson LA Pitis PM Zhang SP 《Bioorganic & medicinal chemistry letters》2004,14(9):2109-2112
A series of N,N-dialkyl-4-(9-aryltropanylidenemethyl)benzamides was prepared. The lead compounds, 15a and 15c, exhibited extremely high affinity for the delta opioid receptor with excellent selectivity versus the micro opioid receptor. They were full agonists at the delta opioid receptor, as assessed by stimulation of GTPgammaS binding, and displayed antinociceptive activity. 相似文献
16.
Cararas SA Izenwasser S Wade D Housman A Verma A Lomenzo SA Trudell ML 《Bioorganic & medicinal chemistry》2011,19(24):7551-7558
The synthesis and structure–activity relationships of 8-substituted-3-[2-(diarylmethoxyethylidenyl)]-8-azabicyclo[3.2.1]octane derivatives were investigated at the dopamine transporter (DAT), the serotonin transporter (SERT) and norepinephrine transporter (NET). The rigid ethylidenyl-8-azabicyclic[3.2.1]octane skeleton imparted modestly stereoselective binding and uptake inhibition at the DAT. Additional structure–activity studies provided a transporter affinity profile that was reminiscent of the structure–activity of GBR 12909. From these studies, the 8-cyclopropylmethyl group has been identified as a unique moiety that imparts high SERT/DAT selectivity. In this study the 8-cyclopropylmethyl derivative 22e (DAT Ki of 4.0 nM) was among the most potent compounds of the series at the DAT and was the most DAT selective ligand of the series (SERT/DAT: 1060). Similarly, the 8-chlorobenzyl derivative 22g (DAT Ki of 3.9 nM) was found to be highly selective for the DAT over the NET (NET/DAT: 1358). 相似文献
17.
Bradley AL Izenwasser S Wade D Klein-Stevens C Zhu N Trudell ML 《Bioorganic & medicinal chemistry letters》2002,12(17):2387-2390
A series of 3alpha-benzyl-8-(diarylmethoxyethyl)-8-azabicyclo[3.2.1]octanes was synthesized and the binding affinities of the compounds were determined at the dopamine transporter. The unsubstituted analogue 7b (K(i)=98nM) was the most potent compound of the series with binding affinity three-times greater than cocaine and only 5-fold less than GBR-12909. The structure-activity data for 7a-f suggests that these compounds may be binding at the dopamine transporter in a similar fashion to GBR 12909. 相似文献
18.
Moree WJ Kataoka K Ramirez-Weinhouse MM Shiota T Imai M Tsutsumi T Sudo M Endo N Muroga Y Hada T Fanning D Saunders J Kato Y Myers PL Tarby CM 《Bioorganic & medicinal chemistry letters》2008,18(6):1869-1873
SAR studies were conducted around lead compound 1 using high-throughput parallel solution and solid phase synthesis. Our lead optimization efforts led to the identification of several CCR2b antagonists with potent activity in both binding and functional assays [Compound 71 CCR2b Binding IC(50) 3.2 nM; MCP-1-Induced Chemotaxis IC(50) 0.83 nM; Ca(2+) Flux IC(50) 7.5 nM]. 相似文献
19.
Thomas JB Atkinson RN Rothman RB Burgess JP Mascarella SW Dersch CM Xu H Carroll FI 《Bioorganic & medicinal chemistry letters》2000,10(11):1281-1284
The tropane derived compounds, 4-[(8-alkyl-8-azabicyclo[3.2.1]octyl-3-yl)-3-arylanilino]-N,N-d iethylbenzamides (5a-d), were synthesized and found to have high affinity and selectivity for the delta receptor. Compounds 5a-d are structurally similar to the full agonist (-)-RTI-5989-54 (3); yet, efficacy studies for compounds in this series (5a-d) reveal greatly diminished agonist activity as well as antagonism not found in piperidine-based compounds like 3. 相似文献
20.
Clark RD Jahangir A Severance D Salazar R Chang T Chang D Jett MF Smith S Bley K 《Bioorganic & medicinal chemistry letters》2004,14(4):1053-1056
On the basis of screening hits (1a,b), a series of selective, high affinity prostacyclin receptor antagonists was developed. The optimized lead compound 25d [(4,5-dihydro-1H-imidazol-2-yl)-[4-(4-isopropoxybenzyl)phenyl]amine] had analgesic activity in the rat. 相似文献