共查询到20条相似文献,搜索用时 46 毫秒
1.
Barlaam B Acton DG Ballard P Bradbury RH Cross D Ducray R Germain H Hudson K Klinowska T Magnien F Ogilvie DJ Olivier A Ross HS Smith R Trigwell CB Vautier M Wright L 《Bioorganic & medicinal chemistry letters》2008,18(6):1799-1803
We have identified a new series of C-5 substituted indazolylaminoquinazolines as potent erbB2 kinase inhibitors. The lead compound 22 showed excellent in vitro potency, good physical properties, acceptable oral pharmacokinetics in rat and dog, and low human in vitro clearance. It showed at least equivalent activity dose for dose compared to lapatinib in various erbB2- or EGFR-driven xenograft models after chronic oral administration. 相似文献
2.
Timothy J. Miles Alan J. Hennessy Ben Bax Gerald Brooks Barry S. Brown Pamela Brown Nathalie Cailleau Dongzhao Chen Steven Dabbs David T. Davies Joel M. Esken Ilaria Giordano Jennifer L. Hoover Jianzhong Huang Graham E. Jones Senthill K. Kusalakumari Sukmar Claus Spitzfaden Roger E. Markwell Neil D. Pearson 《Bioorganic & medicinal chemistry letters》2013,23(19):5437-5441
During the course of our research to find novel mode of action antibacterials, we discovered a series of hydroxyl tricyclic compounds that showed good potency against Gram-positive and Gram-negative pathogens. These compounds inhibit bacterial type IIA topoisomerases. Herein we will discuss structure–activity relationships in this series and report advanced studies on compound 1 (GSK966587) which demonstrates good PK and in vivo efficacy properties. X-ray crystallographic studies were used to provide insight into the structural basis for the difference in antibacterial potency between enantiomers. 相似文献
3.
Discovery and synthesis of 6,7,8,9-tetrahydro-5H-pyrimido-[4,5-d]azepines as novel TRPV1 antagonists
Hawryluk NA Merit JE Lebsack AD Branstetter BJ Hack MD Swanson N Ao H Maher MP Bhattacharya A Wang Q Freedman JM Scott BP Wickenden AD Chaplan SR Breitenbucher JG 《Bioorganic & medicinal chemistry letters》2010,20(23):7137-7141
Utilization of a tetrahydro-pyrimdoazepine core as a bioisosteric replacement for a piperazine-urea resulted in the discovery a novel series of potent antagonists of TRPV1. The tetrahydro-pyrimdoazepines have been identified as having good in vitro and in vivo potency and acceptable physical properties. 相似文献
4.
Simon Peace Joanne Philp Carl Brooks Val Piercy Kitty Moores Chris Smethurst Steve Watson Simon Gaines Mara Zippoli Claudette Mookherjee Robert Ife 《Bioorganic & medicinal chemistry letters》2010,20(13):3961-3964
A series of sulfonamide CCR2 antagonists was identified by high-throughput screening. Management of molecular weight and physical properties, in particular moderation of lipophilicity and study of pKa, yielded highly potent CCR2 antagonists exhibiting good pharmacokinetic properties and improved potency in the presence of human plasma. 相似文献
5.
Takano Y Shiga F Asano J Hori W Anraku T Uno T 《Bioorganic & medicinal chemistry letters》2004,14(20):5107-5111
We describe the synthesis, physicochemical, and biological properties of a novel series of 7-imidazolyl-6-trifluoromethyl quinoxalinecarboxylic acids with a substituted phenyl group attached through a urethane linkage at the C-7 position. We found that the introduction of trifluoromethyl group at the C-6 position brought about good biological activity and physicochemical properties. Among them, compound 9k (KRP-199), which has a 4-carboxyphenyl group, was found to possess high potency and selectivity for the AMPA-R in vitro and to exhibit good neuroprotective effects in vivo. Furthermore, the compound showed good physicochemical properties such as stability to light and good solubility in aqueous solutions. 相似文献
6.
Baldwin I Bamborough P Haslam CG Hunjan SS Longstaff T Mooney CJ Patel S Quinn J Somers DO 《Bioorganic & medicinal chemistry letters》2008,18(19):5285-5289
New kinase inhibitors can be found by synthesis of targeted arrays of compounds designed using system-based knowledge as well as through screening focused or diverse compounds. Most array strategies aim to add functionality to a fragment that binds in the purine subpocket of the ATP-site. Here, an alternative pharmacophore-guided array approach is described which set out to discover novel purine subpocket-binding groups. Results are shown for p38alpha and cFMS kinase, for which multiple distinct series with nanomolar potency were discovered. Some of the compounds showed potency in cell-based assays and good pharmacokinetic properties. 相似文献
7.
IH Kim K Nishi T Kasagami C Morisseau JY Liu HJ Tsai BD Hammock 《Bioorganic & medicinal chemistry letters》2012,22(18):5889-5892
Substituted ureas with a carboxylic acid ester as a secondary pharmacophore are potent soluble epoxide hydrolase (sEH) inhibitors. Although the ester substituent imparts better physical properties, such compounds are quickly metabolized to the corresponding less potent acids. Toward producing biologically active ester compounds, a series of esters were prepared and evaluated for potency on the human enzyme, stability in human liver microsomes, and physical properties. Modifications around the ester function enhanced in vitro metabolic stability of the ester inhibitors up to 32-fold without a decrease in inhibition potency. Further, several compounds had improved physical properties. 相似文献
8.
Dudkin VY Wang C Arrington KL Fraley ME Hartman GD Stirdivant SM Drakas RA Rickert K Walsh ES Hamilton K Buser CA Hardwick J Tao W Beck SC Mao X Lobell RB Sepp-Lorenzino L 《Bioorganic & medicinal chemistry letters》2012,22(7):2613-2619
Translation of significant biochemical activity of pyridyl aminothiazole class of Chk1 inhibitors into functional CEA potency required analysis and adjustment of both physical properties and kinase selectivity profile of the series. The steps toward optimization of cellular potency included elimination of CDK7 activity, reduction of molecular weight and polar surface area and increase in lipophilicity of the molecules in the series. 相似文献
9.
Nicholas Stock Christopher Baccei Gretchen Bain Alex Broadhead Charles Chapman Janice Darlington Christopher King Catherine Lee Yiwei Li Daniel S. Lorrain Pat Prodanovich Haojing Rong Angelina Santini Jasmine Zunic Jilly F. Evans John H. Hutchinson Peppi Prasit 《Bioorganic & medicinal chemistry letters》2010,20(1):213-217
A series of potent 5-lipoxygenase-activating protein (FLAP) inhibitors are herein described. SAR studies focused on the discovery of novel alicyclic moieties appended to an indole core to optimize potency, physical properties and off-target activities. Subsequent SAR on the N-benzyl substituent of the indole led to the discovery of compound 39 (AM679) which showed potent inhibition of leukotrienes in human blood and in a rodent bronchoalvelolar lavage (BAL) challenge model. 相似文献
10.
McKerrecher D Allen JV Caulkett PW Donald CS Fenwick ML Grange E Johnson KM Johnstone C Jones CD Pike KG Rayner JW Walker RP 《Bioorganic & medicinal chemistry letters》2006,16(10):2705-2709
The optimisation of a series of glucokinase activators is described, including attempts to uncouple the relationship between potency and plasma protein binding, and to better understand the key pharmacokinetic properties of the series. The use of unbound clearance as an optimisation parameter facilitated the identification of GKA50, a compound which combines excellent potency and pharmacokinetics with good free drug levels and solubility, and exhibits in vivo efficacy at 1mg/kg po in an acute rat OGTT model. 相似文献
11.
Takano Y Shiga F Asano J Hori W Fukuchi K Anraku T Uno T 《Bioorganic & medicinal chemistry》2006,14(3):776-792
We describe the design, synthesis, and physicochemical and biological properties of a novel series of 7-heterocycle-6-trifluoromethyl-3-oxoquinoxaline-2-carboxylic acids bearing a substituted phenyl group joined through a urethane or urea linkage to the heterocycle at the 7 position. Introduction of the trifluoromethyl group at the 6 position conferred good biological activity, including neuroprotective effects, as well as good physicochemical properties. In terms of alpha-amino-3-hydroxy-5-methylisoxazole propionate receptor (AMPA-R) affinity, a urea linkage was equivalent to a urethane linkage and a pyrrole ring at the 7 position reduced affinity in comparison with an imidazole ring. Among this series, compound 14h (KRP-199), which has a 4-carboxyphenyl group joined through a urethane linkage to a 7-imidazolyl heterocycle, was found to possess high potency and selectivity for the AMPA-R in vitro and to exhibit good neuroprotective effects in vivo. Furthermore, the compound showed good physicochemical properties, including stability to light and good solubility in aqueous solutions. 相似文献
12.
Takano Y Shiga F Asano J Ando N Uchiki H Fukuchi K Anraku T 《Bioorganic & medicinal chemistry》2005,13(20):5841-5863
We describe the design, synthesis, and biological properties of a novel series of 7-substituted 6-nitro-3-oxoquinoxaline-2-carboxylic acids. After designing, studying the structure-activity relationships, and evaluating the properties of various compounds, we found that 7-heterocyclic-6-nitro-3-oxoquinoxaline-2-carboxylic acids that contain a substituted phenyl group linked through urethane at the 7 position possess good alpha-amino-3-hydroxy-5-methylisoxazole propionate receptor (AMPA-R) antagonistic activity. Among the compounds tested, compound 29p (GRA-293), which has a 4-carboxy group on the terminal phenyl moiety, exhibited high potency and selectivity for the AMPA-R in vitro and good neuroprotective efficacy in vivo. It also showed good aqueous solubility. 相似文献
13.
14.
Miles TJ Barfoot C Brooks G Brown P Chen D Dabbs S Davies DT Downie DL Eyrisch S Giordano I Gwynn MN Hennessy A Hoover J Huang J Jones G Markwell R Rittenhouse S Xiang H Pearson N 《Bioorganic & medicinal chemistry letters》2011,21(24):7483-7488
As part of our wider efforts to exploit novel mode of action antibacterials, we have discovered a series of cyclohexyl-amide compounds that has good Gram positive and Gram negative potency. The mechanism of action is via inhibition of bacterial topoisomerases II and IV. We have investigated various subunits in this series and report advanced studies on compound 7 which demonstrates good PK and in vivo efficacy properties. 相似文献
15.
Geng B Breault G Comita-Prevoir J Petrichko R Eyermann C Lundqvist T Doig P Gorseth E Noonan B 《Bioorganic & medicinal chemistry letters》2008,18(15):4368-4372
An early SAR study of a screening hit series has generated a series of 9-benzyl purines as inhibitors of bacterial glutamate racemase (MurI) with micromolar enzyme potency and improved physical properties. X-ray co-crystal EI structures were obtained. 相似文献
16.
Stachel SJ Steele TG Petrocchi A Haugabook SJ McGaughey G Katharine Holloway M Allison T Munshi S Zuck P Colussi D Tugasheva K Wolfe A Graham SL Vacca JP 《Bioorganic & medicinal chemistry letters》2012,22(1):240-244
We have developed a novel series of pyrrolidine derived BACE-1 inhibitors. The potency of the weak initial lead structure was enhanced using library-based SAR methods. The series was then further advanced by rational design while maintaining a minimal ligand binding efficiency threshold. Ultimately, the co-crystal structure was obtained revealing that these inhibitors interacted with the enzyme in a unique fashion. In all, the potency of the series was enhanced by 4 orders of magnitude from the HTS lead with concomitant increases in physical properties needed for series advancement. The progression of these developments in a systematic fashion is described. 相似文献
17.
Penning TD Khilevich A Chen BB Russell MA Boys ML Wang Y Duffin T Engleman VW Finn MB Freeman SK Hanneke ML Keene JL Klover JA Nickols GA Nickols MA Rader RK Settle SL Shannon KE Steininger CN Westlin MM Westlin WF 《Bioorganic & medicinal chemistry letters》2006,16(12):3156-3161
We describe a series of pyrazole and isoxazole analogs as antagonists of the alpha(v)beta3 receptor. Compounds showed low to sub-nanomolar potency against alpha(v)beta3, as well as good selectivity against alpha(IIb)beta3. In HT29 cells, most analogs also demonstrated significant selectivity against alpha(v)beta6. Several compounds showed good pharmacokinetic properties in rats, in addition to anti-angiogenic activity in a mouse corneal micropocket model. Compounds were synthesized in a straightforward manner from readily available glutarate precursors. 相似文献
18.
Atwal KS Ahmad S Ding CZ Stein PD Lloyd J Hamann LG Green DW Ferrara FN Wang P Rogers WL Doweyko LM Miller AV Bisaha SN Schmidt JB Li L Yost KJ Lan HJ Madsen CS 《Bioorganic & medicinal chemistry letters》2004,14(4):1027-1030
A series of substituted guanidine derivatives were prepared and evaluated as potent and selective inhibitors of mitochondrial F(1)F(0) ATP hydrolase. The initial thiourethane derived lead molecules possessed intriguing in vitro pharmacological profiles, though contained moieties considered non-drug-like. Analogue synthesis efforts led to compounds with maintained potency and superior physical properties. Small molecules in this series which potently and selectivity inhibit ATP hydrolase and not ATP synthase may have utility as cardioprotective agents. 相似文献
19.
David M. Rotstein Stephen D. Gabriel Ferenc Makra Lubov Filonova Shelley Gleason Christine Brotherton-Pleiss Lina Q. Setti Alejandra Trejo-Martin Eun Kyung Lee Surya Sankuratri Changhua Ji Andre deRosier Marianna Dioszegi Gabrielle Heilek Andreas Jekle Pamela Berry Paul Weller Cheng-I. Mau 《Bioorganic & medicinal chemistry letters》2009,19(18):5401-5406
A novel series of CCR5 antagonists has been identified, utilizing leads from high-throughput screening which were further modified based on insights from competitor molecules. Lead optimization was pursued by balancing opposing trends of metabolic stability and potency. Selective and potent analogs with good pharmacokinetic properties were successfully developed. 相似文献
20.
Simona Bindi Daniele Fancelli Cristina Alli Daniela Berta Jay A. Bertrand Alexander D. Cameron Paolo Cappella Patrizia Carpinelli Giovanni Cervi Valter Croci Matteo D’Anello Barbara Forte M. Laura Giorgini Aurelio Marsiglio Juergen Moll Enrico Pesenti Valeria Pittalà Maurizio Pulici Federico Riccardi-Sirtori Fulvia Roletto Paola Vianello 《Bioorganic & medicinal chemistry》2010,18(19):7113-7120
A novel series of 3-amino-1H-thieno[3,2-c]pyrazole derivatives demonstrating high potency in inhibiting Aurora kinases was developed. Here we describe the synthesis and a preliminary structure–activity relationship, which led to the discovery of a representative compound (38), which showed low nanomolar inhibitory activity in the anti-proliferation assay and was able to block the cell cycle in HCT-116 cell line. This compound demonstrated favorable pharmacokinetic properties and good efficacy in the HL-60 xenograft tumor model. 相似文献