共查询到20条相似文献,搜索用时 0 毫秒
1.
Andrew S. Felts Sam A. Saleh Uyen Le Alice L. Rodriguez C. David Weaver P. Jeffrey Conn Craig W. Lindsley Kyle A. Emmitte 《Bioorganic & medicinal chemistry letters》2009,19(23):6623-6626
A high-throughput cell-based screen identified a series of 6-substituted-4-anilinoquinazolines as non-competitive antagonists of metabotropic glutamate receptor 5 (mGlu5). This Letter describes the SAR of this series and the profile of selected compounds in selectivity and radioligand binding assays. 相似文献
2.
Ya Zhou Alice L. Rodriguez Richard Williams C. David Weaver P. Jeffrey Conn Craig W. Lindsley 《Bioorganic & medicinal chemistry letters》2009,19(23):6502-6506
This Letter describes the discovery and SAR of three novel series of mGluR5 non-competitive antagonists/negative allosteric modulators (NAMs) not based on manipulation of an MPEP/MTEP chemotype identified by a functional HTS approach. This work demonstrates fundamentally new mGluR5 NAM chemotypes with submicromolar potencies, and further examples of a mode of pharmacology ‘switch’ to provide PAMs with a non-MPEP scaffold. 相似文献
3.
János Galambos Gábor Wágner Katalin Nógrádi Attila Bielik László Molnár Amrita Bobok Attila Horváth Béla Kiss Sándor Kolok József Nagy Dalma Kurkó Mónika L. Bakk Mónika Vastag Katalin Sághy István Gyertyán Krisztina Gál István Greiner Zsolt Szombathelyi György M. Keserű György Domány 《Bioorganic & medicinal chemistry letters》2010,20(15):4371-4375
Hit-to-lead optimization of a HTS hit led to new carbamoyloxime derivatives. After identification of an advanced hit (8d) the CYP enzyme inhibitory activity of this class of compounds was successfully eliminated. Systematic exploration of different parts of the advanced hit led us to some promising lead compounds with mGluR5 affinities comparable to that of MPEP. 相似文献
4.
Alagille D Baldwin RM Roth BL Wroblewski JT Grajkowska E Tamagnan GD 《Bioorganic & medicinal chemistry letters》2005,15(4):945-949
We described the synthesis and biological evaluation of MPEP analogs functionalized at the position 3 of the phenyl ring. The results point out the limitation in the choice of a functional group at this position; the only substituents leading to retention of activity are NO(2) (IC(50)=13 nM) and CN (IC(50)=8 nM). 相似文献
5.
Owen DR Dodd PG Gayton S Greener BS Harbottle GW Mantell SJ Maw GN Osborne SA Rees H Ringer TJ Rodriguez-Lens M Smith GF 《Bioorganic & medicinal chemistry letters》2007,17(2):486-490
A series of novel mGluR1 antagonists have been prepared. Incorporation of fragments derived from weak lead matter into a library led to enhanced potency in a new chemical series. A chemistry driven second library iteration, covering a greatly enhanced area of chemical space, maintained good potency and introduced metabolic stability. 相似文献
6.
Sams AG Mikkelsen GK Brodbeck RM Pu X Ritzén A 《Bioorganic & medicinal chemistry letters》2011,21(11):3407-3410
A series of metabotropic glutamate 5 receptor (mGluR5) allosteric ligands with positive, negative or no modulatory efficacy is described. The ability of this series to yield both mGluR5 PAMs and NAMs with single-digit nanomolar potency is unusual, and the underlying SAR is detailed. 相似文献
7.
Micheli F Fabio RD Cavanni P Rimland JM Capelli AM Chiamulera C Corsi M Corti C Donati D Feriani A Ferraguti F Maffeis M Missio A Ratti E Paio A Pachera R Quartaroli M Reggiani A Sabbatini FM Trist DG Ugolini A Vitulli G 《Bioorganic & medicinal chemistry》2003,11(2):171-183
Metabotropic glutamate receptors (mGluRs) are an unusual family of G-protein coupled receptor (GPCR), and are characterised by a large extracellular N-terminal domain that contains the glutamate binding site. We have identified a new class of non-competitive metabotropic glutamate receptor 1 (mGluR1) antagonists, 2,4-dicarboxy-pyrroles which are endowed with nanomolar potency. They interact within the 7 transmembrane (7TM) domain of the receptor and show antinociceptive properties when tested in a number of different animal models. 相似文献
8.
Manuel Koller David A. Carcache David Orain Peter Ertl Dirk Behnke Sandrine Desrayaud Grit Laue Ivo Vranesic 《Bioorganic & medicinal chemistry letters》2012,22(20):6454-6459
1H-pyrrolo[2,3-c]pyridine-7-carboxamides constitute a new series of allosteric mGluR5 antagonists. Variation of the substituents attached to the heterocyclic scaffold allowed to improve the physico-chemical parameters for optimization of the aqueous solubility while retaining high in vitro potency. 相似文献
9.
Stephanie Brumfield Peter Korakas Lisa S. Silverman Deen Tulshian Julius J. Matasi Li Qiang Chad E. Bennett Duane A. Burnett William J. Greenlee Chad E. Knutson Wen-Lian Wu T.K. Sasikumar Martin Domalski Rosalia Bertorelli Mariagrazia Grilli Gianluca Lozza Angelo Reggiani Cheng Li 《Bioorganic & medicinal chemistry letters》2012,22(23):7223-7226
High throughput screening identified the pyridothienopyrimidinone 1 as a ligand for the metabotropic glutamate receptor 1 (mGluR1 = 10 nM). Compound 1 has an excellent in vivo profile; however, it displays unfavorable pharmacokinetic issues and metabolic stability. Therefore, using 1 as a template, novel analogues (10i) were prepared. These analogues displayed improved oral exposure and activity in the Spinal Nerve Ligation (SNL) pain model. 相似文献
10.
Alice L. Rodriguez Ya Zhou Richard Williams C. David Weaver Paige N. Vinson Eric S. Dawson Thomas Steckler Hilde Lavreysen Claire Mackie José M. Bartolomé Gregor J. Macdonald J. Scott Daniels Colleen M. Niswender Carrie K. Jones P. Jeffrey Conn Craig W. Lindsley Shaun R. Stauffer 《Bioorganic & medicinal chemistry letters》2012,22(24):7388-7392
Herein we report the discovery and SAR of a novel series of non-MPEP site metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs) based on an aryl glycine sulfonamide scaffold. This series represents a rare non-MPEP site mGlu5 PAM chemotype. 相似文献
11.
Zhong-Yue Sun Zhaoning Zhu Yuanzan Ye Brian McKittrick Michael Czarniecki William Greenlee Deborra Mullins Mario Guzzi 《Bioorganic & medicinal chemistry letters》2009,19(23):6801-6805
A class of novel 2-aminobenzothiazoles have been identified as NPY Y1 antagonists. Various N-heterocyclic substituted aminophenethyl-2-aminobenzothiazole analogs were synthesized to explore the SAR. Isothiourea analogs and ligands with high potency (Ki 30 nM) have been identified. 相似文献
12.
《Bioorganic & medicinal chemistry letters》2014,24(4):1239-1242
SAR study of 5-aminooctahydrocyclopentapyrrole-3a-carboxamide scaffold led to identification of several CCR2 antagonists with potent activity in both binding and functional assays. Their cardiovascular safety and pharmacokinetic properties were also evaluated. 相似文献
13.
Eastman B Chen C Smith ND Poon S Chung J Reyes-Manalo G Cosford ND Munoz B 《Bioorganic & medicinal chemistry letters》2004,14(22):5485-5488
The SAR of the lead compounds 2a and 2b was rapidly explored. Utilizing a parallel solution-phase Suzuki coupling approach, in tandem with strong cation exchange resin (SCX) purification afforded the desired focused library. The library was evaluated in vitro, a ninefold potency increase was achieved and the preference for ortho substitution of moderate steric bulk of the fourth, phenyl ring was identified. In addition, dimethylisoxazole, as a heterocyclic replacement for the phenylic ring of the lead compound, was also identified by this approach. 相似文献
14.
M Pietraszek Z Rogóz S Wolfarth K Ossowska 《Journal of physiology and pharmacology》2004,55(3):587-593
Potential antipsychotic effects of a selective non-competitive antagonist of metabotropic glutamate receptor 5 (mGluR5), 2-methyl-6-phenylethynylpyridine (MPEP), was examined in two commonly used screening tests: (1) the hyperactivity induced by an NMDA receptor antagonist phencyclidine (PCP), and (2) the hyperactivity induced by an indirect dopamine agonist, D-amphetamine. PCP was administered at a dose of 2.5 mg/kg s.c. and D-amphetamine was given at a dose of 1 mg/kg s.c. MPEP (5 mg/kg i.p.) significantly enhanced the locomotor activity increased by PCP, but inhibited amphetamine-induced hyperactivity. The opposite effect of MPEP in the two above-mentioned models questions significance of the blockade of mGluR5 receptors to antipsychotic effects. 相似文献
15.
Ian Rilatt Etienne Mirabel Bruno Le Grand Michel Perez 《Bioorganic & medicinal chemistry letters》2010,20(3):903-906
High-throughput screening resulted in the identification of a small molecule inhibitor of PAR1. Optimisation of the initial hit led to the discovery of compounds 34 and 49, which displayed antithrombotic activity in an arteriovenous shunt model in the rat after iv administration. 相似文献
16.
Li-Huai Qin Zhi-Long Wang Xin Xie Ya-Qiu Long 《Bioorganic & medicinal chemistry》2018,26(12):3559-3572
The chemokine CC receptor subtype 2 (CCR2) has attracted intensive interest for drug development in diverse therapeutic areas, including chronic inflammatory diseases, diabetes, neuropathic pain, atherogenesis and cancer. By employing a cut-and-sew scaffold hopping strategy, we identified an active scaffold of 3,4-dihydro-2,6-naphthyridin-1(2H)-one as the central pharmacophore to derive novel CCR2 antagonists. Systematic structure–activity relationship study with respect to the ring size and the substitution on the naphthyridinone ring gave birth to 1-arylamino-6-alkylheterocycle-6,7,8,9-tetrahydro-5H-pyrido[4,3-c]azepin-5-ones as a brand new chemotype of CCR2 antagonists with nanomolar inhibitory activity. The best antagonism activity in this series was exemplified by compound 13a, which combined the optimal substitutions of 3,4-dichlorophenylamino at C-1 and 3-(4-(N-methylmethylsulfonamido)piperidin-1-yl)propyl at N-6 position, leading to an IC50 value of 61?nM and 10-fold selectivity for CCR2 over CCR5. Efficient and general synthesis was established to construct the innovative core structure and derive the compound collections. This is the first report on our designed 6,7,8,9-tetrahydro-5H-pyrido[4,3-c]azepin-5-one as novel CCR2 antagonist scaffold and its synthesis. 相似文献
17.
Hammerland LG Johansson M Malmström J Mattsson JP Minidis AB Nilsson K Peterson A Wensbo D Wållberg A Osterlund K 《Bioorganic & medicinal chemistry letters》2006,16(9):2467-2469
Structure-activity relationship investigations of the thiopyrimidine (1), an HTS hit with micromolar activity as a metabotropic glutamate receptor 5 (mGluR5) antagonist, led to compounds with sub-micromolar activity. 相似文献
18.
Li GB Yang LL Feng S Zhou JP Huang Q Xie HZ Li LL Yang SY 《Bioorganic & medicinal chemistry letters》2011,21(6):1736-1740
Development of glutamate non-competitive antagonists of mGluR1 (Metabotropic glutamate receptor subtype 1) has increasingly attracted much attention in recent years due to their potential therapeutic application for various nervous disorders. Since there is no crystal structure reported for mGluR1, ligand-based virtual screening (VS) methods, typically pharmacophore-based VS (PB-VS), are often used for the discovery of mGluR1 antagonists. Nevertheless, PB-VS usually suffers a lower hit rate and enrichment factor. In this investigation, we established a multistep ligand-based VS approach that is based on a support vector machine (SVM) classification model and a pharmacophore model. Performance evaluation of these methods in virtual screening against a large independent test set, M-MDDR, show that the multistep VS approach significantly increases the hit rate and enrichment factor compared with the individual SB-VS and PB-VS methods. The multistep VS approach was then used to screen several large chemical libraries including PubChem, Specs, and Enamine. Finally a total of 20 compounds were selected from the top ranking compounds, and shifted to the subsequent in vitro and in vivo studies, which results will be reported in the near future. 相似文献
19.
Li G Stamford AW Huang Y Cheng KC Cook J Farley C Gao J Ghibaudi L Greenlee WJ Guzzi M van Heek M Hwa JJ Kelly J Mullins D Parker EM Wainhaus S Zhang X 《Bioorganic & medicinal chemistry letters》2008,18(3):1146-1150
We have derived a novel series of neuropeptide Y (NPY) Y5 receptor antagonists from the biphenylurea 3. Cyclohexylurea 21c, a member of the series, is a potent NPY Y5 receptor antagonist that exhibits excellent pharmacokinetic parameters in rats and dogs. On chronic oral administration to diet-induced obese rats, 21c displayed an anti-obesity profile, causing a modest reduction in food intake, a significant decrease in body weight gain, a decrease in adipose mass, and an increase in lean tissue mass. 相似文献
20.
Allen S Newhouse B Anderson AS Fauber B Allen A Chantry D Eberhardt C Odingo J Burgess LE 《Bioorganic & medicinal chemistry letters》2004,14(7):1619-1624
Substituted thiazolidinones were identified as CCR4 antagonists from high throughput screening. Subsequent lead optimization efforts resulted in defined structure-activity relationships and the identification of potent antagonists (compounds 90 and 91) that inhibited the chemotaxis of Th2 T-cells in vitro. 相似文献