排序方式: 共有18条查询结果,搜索用时 15 毫秒
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Clarke B Demont E Dingwall C Dunsdon R Faller A Hawkins J Hussain I MacPherson D Maile G Matico R Milner P Mosley J Naylor A O'Brien A Redshaw S Riddell D Rowland P Soleil V Smith KJ Stanway S Stemp G Sweitzer S Theobald P Vesey D Walter DS Ward J Wayne G 《Bioorganic & medicinal chemistry letters》2008,18(3):1017-1021
This paper describes the discovery of non-peptidic, potent, and selective hydroxy ethylamine (HEA) inhibitors of BACE-1 by replacement of the prime side of a lead di-amide 2. Inhibitors with nanosmolar potency and high selectivity were identified. Depending on the nature of the P(1)(') and P(2)(') substituents, two different binding modes were observed in X-ray co-crystal structures. 相似文献
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Federico Antonio Gutiérrez Miceli Adan Domínguez Estudillo Miguel Abud Archila Teresa del Rosario Ayora Talavera Luc Dendooven 《In vitro cellular & developmental biology. Plant》2008,44(1):33-39
Renealmia mexicana (Klotzsch ex. Petersen) is a tropical plant found in southern México with an ornamental value and a potential source of curcuminoids.
Its distribution in Chiapas has decreased because of deforestation and low propagation and germination rate, so a protocol
for in vitro propagation was developed. An orthogonal experimental design of L9 (34) in triplicate was used to investigate the effect of 6-benzyl adenine (BA), indole butyric acid (IBA), silver nitrate (AgNO3), and sucrose on shoot, root, and leaf development of plantlets grown in vitro. Plantlets with well-developed shoots and roots were transferred to pots containing a mixture of peat moss and agrolite for
hardening before transfer to soil. The Murashige and Skoog (Physiol. Plant. 15:473–497, 1962) mineral medium (MS) supplemented
with 4.4 μM BA, 2.5 μM IBA, 11.7 μM AgNO3y and 5.5% (w/v) sucrose gave most shoots, 8.9 μM BA, 2.5 μM IBA, 17.7 μM AgNO3 and 5.5% (w/v) sucrose most roots, and 8.9 μM BA, 4.9 μM IBA, 11.7 μM AgNO3 and 3.0% (w/v) sucrose most leaves, although other combinations were statistically equivalent in each case. Sucrose was the factor that
most explained the variation in the promotion of shoots, roots, and leaves. The protocol developed resulted in up to 100%
survival when plantlets were transferred to soil using AgNO3, confirming that hardening of plantlets in vitro using hormonal stimulation was a suitable strategy to improve acclimatization. 相似文献
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Beswick P Charrier N Clarke B Demont E Dingwall C Dunsdon R Faller A Gleave R Hawkins J Hussain I Johnson CN MacPherson D Maile G Matico R Milner P Mosley J Naylor A O'Brien A Redshaw S Riddell D Rowland P Skidmore J Soleil V Smith KJ Stanway S Stemp G Stuart A Sweitzer S Theobald P Vesey D Walter DS Ward J Wayne G 《Bioorganic & medicinal chemistry letters》2008,18(3):1022-1026
This article is focusing on further optimization of previously described hydroxy ethylamine (HEA) BACE-1 inhibitors obtained from a focused library with the support of X-ray crystallography. Optimization of the non-prime side of our inhibitors and introduction of a 6-membered sultam substituent binding to Asn-294 as well as a fluorine in the C-2 position led to derivatives with nanomolar potency in cell-based assays. 相似文献
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Nicolas Charrier Brian Clarke Leanne Cutler Emmanuel Demont Colin Dingwall Rachel Dunsdon Julie Hawkins Colin Howes Julia Hubbard Ishrut Hussain Graham Maile Rosalie Matico Julie Mosley Alan Naylor Alistair O’Brien Sally Redshaw Paul Rowland Virginie Soleil Kathrine J. Smith Sharon Sweitzer Gareth Wayne 《Bioorganic & medicinal chemistry letters》2009,19(13):3664-3668
Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer’s disease. We have recently disclosed a series of transition-state mimetic BACE-1 inhibitors showing nanomolar potency in cell-based assays. Amongst them, GSK188909 (compound 2) had favorable pharmacokinetics and was the first orally bioavailable inhibitor reported to demonstrate brain amyloid lowering in an animal model. In this Letter, we describe the reasons that led us to favor a second generation of inhibitors for further in vivo studies. 相似文献
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Brian Clarke Leanne Cutler Emmanuel Demont Colin Dingwall Rachel Dunsdon Julie Hawkins Colin Howes Ishrut Hussain Graham Maile Rosalie Matico Julie Mosley Alan Naylor Alistair O’Brien Sally Redshaw Paul Rowland Virginie Soleil Kathrine J. Smith Sharon Sweitzer Pam Theobald David Vesey Gareth Wayne 《Bioorganic & medicinal chemistry letters》2010,20(15):4639-4644
Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer’s disease. Herein, is described a series of potent inhibitors based on an hydroxyethylamine (HEA) transition state mimetic template. These inhibitors interact with the non prime side of the enzyme using a novel edge-to-face interaction with Arg-296. 相似文献
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Nicolas Charrier Brian Clarke Leanne Cutler Emmanuel Demont Colin Dingwall Rachel Dunsdon Julie Hawkins Colin Howes Julia Hubbard Ishrut Hussain Graham Maile Rosalie Matico Julie Mosley Alan Naylor Alistair O’Brien Sally Redshaw Paul Rowland Virginie Soleil Kathrine J. Smith Sharon Sweitzer Gareth Wayne 《Bioorganic & medicinal chemistry letters》2009,19(13):3674-3678
Our first generation of hydroxyethylamine BACE-1 inhibitors proved unlikely to provide molecules that would lower amyloid in an animal model at low oral doses. This observation led us to the discovery of a second generation of inhibitors having nanomolar activity in a cell-based assay and with the potential for improved pharmacokinetic profiles. In this Letter, we describe our successful strategy for the optimization of oral bioavailability and also give insights into the design of compounds with the potential for improved brain penetration. 相似文献
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Clarke B Demont E Dingwall C Dunsdon R Faller A Hawkins J Hussain I MacPherson D Maile G Matico R Milner P Mosley J Naylor A O'Brien A Redshaw S Riddell D Rowland P Soleil V Smith KJ Stanway S Stemp G Sweitzer S Theobald P Vesey D Walter DS Ward J Wayne G 《Bioorganic & medicinal chemistry letters》2008,18(3):1011-1016
Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer's disease. Herein, is described the lead generation effort which resulted, with the support of X-ray crystallography, in the discovery of potent inhibitors based on a hydroxy ethylamine (HEA) transition-state mimetic. These inhibitors were capable of lowering amyloid production in a cell-based assay. 相似文献