共查询到20条相似文献,搜索用时 15 毫秒
1.
James M. Bailey Jackie S. Scott Jonathan B. Basilla Victoria J. Bolton Izzy Boyfield David G. Evans Etienne Fleury Tom D. Heightman Emma M. Jarvie Kirk Lawless Kim L. Matthews Fiona McKay Hindy Mok Alison Muir Barry S. Orlek Gareth J. Sanger Geoffrey Stemp Alexander J. Stevens Mervyn Thompson John Ward Kalindi Vaidya Susan M. Westaway 《Bioorganic & medicinal chemistry letters》2009,19(22):6452-6458
Optimisation of a series of benzazepine sulfonamide hit compounds identified from high throughput screening led to the discovery of a new series of tractable, potent motilin receptor agonists. 相似文献
2.
Lesuisse D Mauger J Nemecek C Maignan S Boiziau J Harlow G Hittinger A Ruf S Strobel H Nair A Ritter K Malleron JL Dagallier A El-Ahmad Y Guilloteau JP Guizani H Bouchard H Venot C 《Bioorganic & medicinal chemistry letters》2011,21(8):2224-2228
A new series of IGF-1R inhibitors related to hydantoins were identified from a lead originating from HTS. Their noncompetitive property as well as their slow binding characteristics provided a series of compounds with unique selectivity and excellent cellular activities. 相似文献
3.
Masood MA Selby MD Bell AS Mansfield AC Gardner M Smith GF Lane C Kenyon-Edwards H Osborne R Jones RM Liu WL Brown CD Clarke N Perrucio F Mowbray CE 《Bioorganic & medicinal chemistry letters》2011,21(21):6591-6595
We describe the identification of a potent, selective lead series that shows antagonism against the human histamine H4 receptor from thirteen actives identified in an HTS as part of a hit to lead program. By focusing on ligand efficiency and concurrently using a diversity based approach, compounds based around 2,4-diaminopyrimidine were identified with compound 25 being quickly shown to be a good lead. It also had the highest ligand efficiency in the series. 相似文献
4.
Jetter MC Youngman MA McNally JJ Zhang SP Dubin AE Nasser N Dax SL 《Bioorganic & medicinal chemistry letters》2004,14(12):3053-3056
Starting from a low micromolar agonist lead identified by high-throughput screening, series of N-isoquinolin-5-yl-N'-aralkyl ureas and analogous amides were developed as potent antagonists of human vanilloid receptor 1 (VR1). The synthesis and structure-activity relationships (SAR) of the series are described. 相似文献
5.
Joshua L Heazlewood 《BBA》2003,1604(3):159-169
The NADH:ubiquinone oxidoreductase of the mitochondrial respiratory chain is a large multisubunit complex in eukaryotes containing 30-40 different subunits. Analysis of this complex using blue-native gel electrophoresis coupled to tandem mass spectrometry (MS) has identified a series of 30 different proteins from the model dicot plant, Arabidopsis, and 24 different proteins from the model monocot plant, rice. These proteins have been linked back to genes from plant genome sequencing and comparison of this dataset made with predicted orthologs of complex I components in these plants. This analysis reveals that plants contain the series of 14 highly conserved complex I subunits found in other eukaryotic and related prokaryotic enzymes and a small set of 9 proteins widely found in eukaryotic complexes. A significant number of the proteins present in bovine complex I but absent from fungal complex I are also absent from plant complex I and are not encoded in plant genomes. A series of plant-specific nuclear-encoded complex I associated subunits were identified, including a series of ferripyochelin-binding protein-like subunits and a range of small proteins of unknown function. This represents a post-genomic and large-scale analysis of complex I composition in higher plants. 相似文献
6.
Austin NE Hadley MS Harling JD Harrington FP Macdonald GJ Mitchell DJ Riley GJ Stean TO Stemp G Stratton SC Thompson M Upton N 《Bioorganic & medicinal chemistry letters》2003,13(10):1627-1629
Starting from a series of 7-linked tetrahydroisoquinoline derivatives, as exemplified by SB-270664, a new series of 8,8-dimethylnaphthyridine compounds has been identified. SAR studies around these attractive leads have provided compounds such as 12 which display excellent anticonvulsant activity and an encouraging pharmacokinetic profile in vivo. 相似文献
7.
Alper PB Marsilje TH Mutnick D Lu W Chatterjee A Roberts MJ He Y Karanewsky DS Chow D Lao J Gerken A Tuntland T Liu B Chang J Gordon P Seidel HM Tian SS 《Bioorganic & medicinal chemistry letters》2008,18(19):5255-5258
A novel series of benzo[a]carbazole-based small molecule agonists of the thrombopoietin (Tpo) receptor is reported. Starting from a 3.4 microM high throughput screen hit, members of this series have been identified which are full agonists with functional potency <50 nM and oral bioavailability in mice. 相似文献
8.
The NADH:ubiquinone oxidoreductase of the mitochondrial respiratory chain is a large multisubunit complex in eukaryotes containing 30-40 different subunits. Analysis of this complex using blue-native gel electrophoresis coupled to tandem mass spectrometry (MS) has identified a series of 30 different proteins from the model dicot plant, Arabidopsis, and 24 different proteins from the model monocot plant, rice. These proteins have been linked back to genes from plant genome sequencing and comparison of this dataset made with predicted orthologs of complex I components in these plants. This analysis reveals that plants contain the series of 14 highly conserved complex I subunits found in other eukaryotic and related prokaryotic enzymes and a small set of 9 proteins widely found in eukaryotic complexes. A significant number of the proteins present in bovine complex I but absent from fungal complex I are also absent from plant complex I and are not encoded in plant genomes. A series of plant-specific nuclear-encoded complex I associated subunits were identified, including a series of ferripyochelin-binding protein-like subunits and a range of small proteins of unknown function. This represents a post-genomic and large-scale analysis of complex I composition in higher plants. 相似文献
9.
Thomson CG Beer MS Curtis NR Diggle HJ Handford E Kulagowski JJ 《Bioorganic & medicinal chemistry letters》2004,14(3):677-680
A series of thiazole based 5HT(7) ligands has been identified from screening. Optimisation of the pendent aryl group and modification of the core gave a related series of high affinity, selective thiopyridine based 5HT(7) ligands, the most active of which behaves as a partial agonist. 相似文献
10.
A several series of low molecular weight 5-HT(2A) leads were identified from an analysis of HTS data, the exploration of SAR and optimization of one series using parallel synthesis are described, affording compound 22 (5-HT(2A) IC(50) 1.1 nM). 相似文献
11.
Rémi Patouret Christelle Doebelin Ruben D. Garcia-Ordonez Mi Ra Chang Claudia Ruiz Michael D. Cameron Patrick R. Griffin Theodore M. Kamenecka 《Bioorganic & medicinal chemistry letters》2018,28(7):1178-1181
Crystallography has identified stearic acid, ALRT 1550 and ATRA as ligands that bind RORβ, however, none of these molecules represent good starting points to develop optimized small molecule modulators. Recently, Compound 1 was identified as a potent dual RORβ and RORγ inverse agonist with no activity towards RORα (Fig. 1). To our knowledge, this is one of only two small molecule RORβ inverse agonists identified in the primary literature from a tractable chemical series and represents an ideal starting point from which to design RORβ-selective modulators. Herein we describe our SAR optimization efforts that led to a series of potent neutral antagonists of RORβ. 相似文献
12.
Finn J Mattia K Morytko M Ram S Yang Y Wu X Mak E Gallant P Keith D 《Bioorganic & medicinal chemistry letters》2003,13(13):2231-2234
Starting with a micromolar lead identified from high-throughput screening, a series of pyrazoles were discovered with significantly improved potency on bacterial methionyl-tRNA synthetase and selectivity over human methionyl-tRNA synthetase. 相似文献
13.
Alan Brown Dave Ellis Olga Wallace Michael Ralph 《Bioorganic & medicinal chemistry letters》2010,20(7):2224-2228
A series of amides were investigated as potential bioisosteres of previously reported triazole Oxytocin antagonists. A range of potent analogues were identified, although SAR for potency and selectivity over the related V1A and V2 receptors was found to be somewhat divergent from that observed for the corresponding triazole series. The high synthetic accessibility of this new amide series also facilitated the identification of a range of alternative left hand side (biaryl replacement) substituents which gave good levels of Oxytocin antagonism. 相似文献
14.
15.
Roach SL Higuchi RI Hudson AR Adams ME Syka PM Mais DE Miner JN Marschke KB Zhi L 《Bioorganic & medicinal chemistry letters》2011,21(1):168-171
We have previously disclosed a series of glucocorticoid receptor (GR) ligands derived from 6-indole-1,2,3,4-tetrahydroquinolines through structure-activity relationship (SAR) of the pendent C6-indole ring. In parallel with this effort, we now report SAR of the tetrahydroquinoline A-ring that identified the importance of a C3 hydroxyl in improving GR selectivity within a series of non-steroidal GR agonists. 相似文献
16.
Morales-Ramos AI Mecom JS Kiesow TJ Graybill TL Brown GD Aiyar NV Davenport EA Kallal LA Knapp-Reed BA Li P Londregan AT Morrow DM Senadhi S Thalji RK Zhao S Burns-Kurtis CL Marino JP 《Bioorganic & medicinal chemistry letters》2008,18(23):6222-6226
High-throughput screening of the GSK compound collection against the P2Y(1) receptor identified a novel series of tetrahydro-4-quinolinamine antagonists. Optimal substitution around the piperidine group was pivotal for ensuring activity. An exemplar analog from this series was shown to inhibit platelet aggregation. 相似文献
17.
A series of ether-, substituted alkyl-, or aryl-linked disaccharide derivatives have been synthesized in relatively good yield and characterized using different spectral techniques including single-crystal X-ray diffraction (XRD). β-Anomeric forms of sugar moiety in these derivatives were identified from 1H NMR studies. The existence of inter- and intramolecular hydrogen bonding interactions were identified from single-crystal XRD studies. 相似文献
18.
Reiter LA Freeman-Cook KD Jones CS Martinelli GJ Antipas AS Berliner MA Datta K Downs JT Eskra JD Forman MD Greer EM Guzman R Hardink JR Janat F Keene NF Laird ER Liras JL Lopresti-Morrow LL Mitchell PG Pandit J Robertson D Sperger D Vaughn-Bowser ML Waller DM Yocum SA 《Bioorganic & medicinal chemistry letters》2006,16(22):5822-5826
Using SAR from two related series of pyrimidinetrione-based inhibitors, compounds with potent MMP-13 inhibition and >100-fold selectivity against other MMPs have been identified. Despite high molecular weights, clogPs, and polar surface areas, the compounds are generally well absorbed and have excellent pharmacokinetic (PK) properties when dosed as sodium salts. In a rat fibrosis model, a compound from the series displayed no fibrosis at exposures many fold greater than its MMP-13 IC50. 相似文献
19.
Gustin DJ Ma Z Min X Li Y Hedberg C Guimaraes C Porter AC Lindstrom M Lester-Zeiner D Xu G Carlson TJ Xiao S Meleza C Connors R Wang Z Kayser F 《Bioorganic & medicinal chemistry letters》2011,21(8):2492-2496
Starting from a series of ureas that were determined to be mechanism-based inhibitors of FAAH, several spirocyclic ureas and lactams were designed and synthesized. These efforts identified a series of novel, noncovalent FAAH inhibitors with in vitro potency comparable to known covalent FAAH inhibitors. The mechanism of action for these compounds was determined through a combination of SAR and co-crystallography with rat FAAH. 相似文献
20.
David A. Scott Kirsten J. Bell Cheryl T. Campbell Donald J. Cook Les A. Dakin David J. Del Valle Lisa Drew Thomas W. Gero Maureen M. Hattersley Charles A. Omer Boris Tyurin Xiaolan Zheng 《Bioorganic & medicinal chemistry letters》2009,19(3):701-705
The optimization of compounds from the 3-amido-4-anilinoquinolines series of CSF-1R kinase inhibitors is described. The series has excellent activity and kinase selectivity. Excellent physical properties and rodent PK profiles were achieved through the introduction of cyclic amines at the quinoline 6-position. Compounds with good activity in a mouse PD model measuring inhibition of pCSF-1R were identified. 相似文献