共查询到20条相似文献,搜索用时 15 毫秒
1.
Rahman SS Coulton S Herdon HJ Joiner GF Jin J Porter RA 《Bioorganic & medicinal chemistry letters》2007,17(6):1741-1745
High throughput screening led to the discovery of a novel series of 1,3-diaminopropan-2-ol sulfonamides as selective GlyT-1 inhibitors. Structure-activity relationships of this novel series and optimisation of the initial hit that led to the identification of (2), a potent and selective GlyT-1 inhibitor, are also presented. 相似文献
2.
Jiwen Liu Zice Fu Yingcai Wang Mike Schmitt Alan Huang Derek Marshall George Tonn Lisa Seitz Tim Sullivan H. Lucy Tang Tassie Collins Julio Medina 《Bioorganic & medicinal chemistry letters》2009,19(22):6419-6423
A series of phenylacetic acid derivatives was discovered as CRTH2 antagonists. Modification of the series led to compounds that are also antagonists of DP. Since activation of CRTH2 and DP are believed to play key roles in mediating responses of asthma and other immune diseases, this series was optimized to increase the dual antagonistic activities and improve pharmacokinetic properties. These efforts led to selection of AMG 009 as a clinical candidate. 相似文献
3.
Zheng X Hodgetts KJ Brielmann H Hutchison A Burkamp F Brian Jones A Blurton P Clarkson R Chandrasekhar J Bakthavatchalam R De Lombaert S Crandall M Cortright D Blum CA 《Bioorganic & medicinal chemistry letters》2006,16(19):5217-5221
Bioisosteric replacement of piperazine with an aryl ring in lead VR1 antagonist 1 led to the biarylamide series. The development of B-ring SAR led to the conformationally constrained analog 70. The resulting aminoquinazoline 70 represents a novel VR1 antagonist with improved in vitro potency and oral bioavailability vs the analogous compounds from the lead series. 相似文献
4.
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
5.
Hagmann WK Durette PL Lanza T Kevin NJ de Laszlo SE Kopka IE Young D Magriotis PA Li B Lin LS Yang G Kamenecka T Chang LL Wilson J MacCoss M Mills SG Van Riper G McCauley E Egger LA Kidambi U Lyons K Vincent S Stearns R Colletti A Teffera J Tong S Fenyk-Melody J Owens K Levorse D Kim P Schmidt JA Mumford RA 《Bioorganic & medicinal chemistry letters》2001,11(20):2709-2713
Directed screening of a carboxylic acid-containing combinatorial library led to the discovery of potent inhibitors of the integrin VLA-4. Subsequent optimization by solid-phase synthesis afforded a series of sulfonylated dipeptide inhibitors with structural components that when combined in a single hybrid molecule gave a sub-nanomolar inhibitor as a lead for medicinal chemistry. Preliminary metabolic studies led to the discovery of substituted biphenyl derivatives with low picomolar activities. SAR and pharmacokinetic characterization of this series are presented. 相似文献
6.
Guo C Pairish M Linton A Kephart S Ornelas M Nagata A Burke B Dong L Engebretsen J Fanjul AN 《Bioorganic & medicinal chemistry letters》2012,22(7):2572-2578
Oxobenzimidazoles (e.g., 1), a novel series of androgen receptor (AR) antagonists, were discovered through de novo design guided by structure-based drug design. The compounds in this series were reasonably permeable and metabolically stable, but suffered from poor solubility. The incorporation of three dimensional structural features led to improved solubility. In addition, the observation of a 'flipped' binding mode of an oxobenzimidazole analog in an AR ligand binding domain (LBD) model, led to the design and discovery of the novel oxindole series (e.g., 2) that is a potent full antagonist of AR. 相似文献
7.
Brown A Brown L Ellis D Puhalo N Smith CR Wallace O Watson L 《Bioorganic & medicinal chemistry letters》2008,18(15):4278-4281
A novel series of Oxytocin antagonists are described. This series was identified through pharmacophoric overlap of in-house and literature antagonists. Subsequent optimization led to a series of potent, selective antagonists. Several analogues displayed oral bioavailability in vivo in the rat. 相似文献
8.
McClure KJ Maher M Wu N Chaplan SR Eckert WA Lee DH Wickenden AD Hermann M Allison B Hawryluk N Breitenbucher JG Grice CA 《Bioorganic & medicinal chemistry letters》2011,21(18):5197-5201
The discovery of a series of novel, potent, and selective blockers of the cyclic nucleotide-modulated channel HCN1 is disclosed. Here we report an SAR study around a series of selective blockers of the HCN1 channel. Utilization of a high-throughput VIPR assay led to the identification of a novel series of 2,2-disubstituted indane derivatives, which had moderate selectivity and potency at HCN1. Optimization of this hit led to the identification of the potent, 1,1-disubstituted cyclohexane HCN1 blocker, 2-ethoxy-N-((1-(4-isopropylpiperazin-1-yl)cyclohexyl)methyl)benzamide. The work leading to the discovery of this compound is described herein. 相似文献
9.
Wei RG Arnaiz DO Chou YL Davey D Dunning L Lee W Lu SF Onuffer J Ye B Phillips G 《Bioorganic & medicinal chemistry letters》2007,17(1):231-234
High throughput screening (HTS) led to the identification of the guanylhydrazone of 2-(4-chlorobenzyloxy)-5-bromobenzaldehyde as a CCR5 receptor antagonist. Initial modifications of the guanylhydrazone series indicated that substitution of the benzyl group at the para-position was well tolerated. Substitution at the 5-position of the central phenyl ring was critical for potency. Replacement of the guanylhydrazone group led to the discovery of a novel series of CCR5 antagonists. 相似文献
10.
Javier de Vicente Robert T. Hendricks David B. Smith Jay B. Fell John Fischer Stacey R. Spencer Peter J. Stengel Peter Mohr John E. Robinson James F. Blake Ramona K. Hilgenkamp Calvin Yee George Adjabeng Todd R. Elworthy Jim Li Beihan Wang Joe T. Bamberg Seth F. Harris April Wong Vincent J.P. Leveque Robert Farrell 《Bioorganic & medicinal chemistry letters》2009,19(19):5652-5656
A series of benzo[d]isothiazole-1,1-dioxides were designed and evaluated as inhibitors of HCV polymerase NS5B. Structure-based design led to the incorporation of a high affinity methyl sulfonamide group. Structure–activity relationship (SAR) studies of this series revealed analogues with submicromolar potencies in the HCV replicon assay and moderate pharmacokinetic properties. SAR studies combined with structure based drug design focused on the sulfonamide region led to a novel and potent cyclic analogue. 相似文献
11.
Jetter MC McNally JJ Youngman MA McDonnell ME Dubin AE Nasser N Zhang SP Codd EE Colburn RW Stone DR Brandt MR Flores CM Dax SL 《Bioorganic & medicinal chemistry letters》2008,18(8):2730-2734
High throughput screening of our compound library revealed a series of N-pyridyl-3-benzamides as low micromolar agonists of the human TRPV1 receptor. Synthesis of analogs in this series led to the discovery of a series of N-quinolin-3-yl-benzamides as low nanomolar antagonists of human TRPV1. 相似文献
12.
Epple R Russo R Azimioara M Cow C Xie Y Wang X Wityak J Karanewsky D Gerken A Iskandar M Saez E Martin Seidel H Tian SS 《Bioorganic & medicinal chemistry letters》2006,16(16):4376-4380
We report the identification of a novel series of trisubstituted isoxazoles as PPAR activators from a high-throughput screen. A series of structural optimizations led to improved efficacy and excellent functional receptor selectivity for PPARdelta. The isoxazoles represent a series of agonists which display a scaffold that lies outside the typical PPAR agonist motif. 相似文献
13.
John Liddle Paul Bamborough Michael D. Barker Sebastien Campos Rick P.C. Cousins Geoffrey J. Cutler Heather Hobbs Duncan S. Holmes Chris Ioannou Geoff W. Mellor Mary A. Morse Jeremy J. Payne John M. Pritchard Kathryn J. Smith Daniel T. Tape Caroline Whitworth Richard A. Williamson 《Bioorganic & medicinal chemistry letters》2009,19(9):2504-2508
The synthesis and SAR of a novel series of IKK2 inhibitors are described. Modification around the hinge binding region of the 7-azaindole led to a series of potent and selective inhibitors with good cellular activity. 相似文献
14.
Jutta Wanner Lijing Chen Rémy C. Lemoine Rama Kondru Andreas Jekle Gabrielle Heilek André deRosier Changhua Ji Pamela W. Berry David M. Rotstein 《Bioorganic & medicinal chemistry letters》2010,20(22):6802-6807
Replacement of a secondary amide with a piperidine or azetidine moiety in a series of CCR5 antagonists led to the discovery of compounds with increased intrinsic permeability. This effort led to the identification of a potent CCR5 antagonist which exhibited an improved in vivo pharmacokinetic profile. 相似文献
15.
Mark J. Wall Nalin L. Subasinghe Michael P. Winters Mary Lou Lubin Michael F.A. Finley Ning Qin Michael R. Brandt Michael P. Neeper Craig R. Schneider Raymond W. Colburn Christopher M. Flores Zhihua Sui 《Bioorganic & medicinal chemistry letters》2018,28(23-24):3780-3783
A novel series of pyrazolyltetrahydropyran N-type calcium channel blockers are described. Structural modifications of the series led to potent compounds in both a cell-based fluorescent calcium influx assay and a patch clamp electrophysiology assay. Representative compounds from the series were bioavailable and showed efficacy in the rat CFA and CCI models of inflammatory and neuropathic pain. 相似文献
16.
Lewis SJ Smith AL Neduvelil JG Stevenson GI Lindon MJ Jones AB Shearman MS Beher D Clarke E Best JD Peachey JE Harrison T Castro JL 《Bioorganic & medicinal chemistry letters》2005,15(2):373-378
A new series of gamma-secretase inhibitors was developed from an in-house screening hit based on a benzobicyclo[4.2.1]nonane core. Lead optimisation studies led to the development of a series of potent inhibitors and in vivo efficacy was demonstrated. 相似文献
17.
Kopecky DJ Jiao XY Fisher B McKendry S Labelle M Piper DE Coward P Shiau AK Escaron P Danao J Chai A Jaen J Kayser F 《Bioorganic & medicinal chemistry letters》2012,22(7):2407-2410
Structural modification of a series of dual LXRα/β agonists led to the identification of a new class of LXRβ partial agonists. An X-ray co-crystal structure shows that a representative member of this series, pyrrole 5, binds to LXRβ with a reversed orientation compared to 1. 相似文献
18.
Jin J Dhanak D Knight SD Widdowson K Aiyar N Naselsky D Sarau HM Foley JJ Schmidt DB Bennett CD Wang B Warren GL Moore ML Keenan RM Rivero RA Douglas SA 《Bioorganic & medicinal chemistry letters》2005,15(13):3229-3232
High throughput screening of the corporate compound collection led to the discovery of a novel series of substituted aminoalkoxybenzyl pyrrolidines as human urotensin-II receptor antagonists. The synthesis, initial structure-activity relationships, and optimization of the initial hit that led to the identification of a truncated sub-series, represented by SB-436811 (1a), are described. 相似文献
19.
R Kuang H Wu PC Ting RG Aslanian J Cao DW Kim JF Lee J Schwerdt G Zhou R Jason Herr AJ Zych J Yang SQ Lam DM Jenkins SA Sakwa S Wainhaus TA Black A Cacciapuoti PM McNicholas Y Xu SS Walker 《Bioorganic & medicinal chemistry letters》2012,22(16):5268-5271
A detailed structure-activity relationship study of a novel series of pyridazine-based small molecule glucan synthase inhibitors is described. The optimization of the PK profile of this series led to the discovery of compound 11g, which demonstrated in vivo potency ip in a lethal fungal infection model. 相似文献
20.
Lan Pham Khanh Patrick Dallemagne Henriette Landelle Sylvain Rault 《Journal of enzyme inhibition and medicinal chemistry》2013,28(6):439-442
Application of the bivalent approach to the cyclopenta [c] thiophene series led to a potent cytotoxic dimer. 相似文献