共查询到20条相似文献,搜索用时 15 毫秒
1.
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
2.
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
3.
Nicolas Charrier Brian Clarke Emmanuel Demont Colin Dingwall Rachel Dunsdon Julie Hawkins 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 Pam Theobald David Vesey Gareth Wayne 《Bioorganic & medicinal chemistry letters》2009,19(13):3669-3673
Our first generation of hydroxyethylamine transition-state mimetic BACE-1 inhibitors allowed us to validate BACE-1 as a key target for Alzheimer’s disease by demonstrating amyloid lowering in an animal model, albeit at rather high doses. Finding a molecule from this series which was active at lower oral doses proved elusive and demonstrated the need to find a novel series of inhibitors with improved pharmacokinetics. This Letter describes the discovery of such inhibitors. 相似文献
4.
Raymond A. Ng Minghua Sun Simeon Bowers Roy K. Hom Gary D. Probst Varghese John Lawrence Y. Fang Michel Maillard Andrea Gailunas Louis Brogley R. Jeffrey Neitz Jay S. Tung Michael A. Pleiss Andrei W. Konradi Hing L. Sham Michael S. Dappen Marc Adler Nanhua Yao Ted A. Yednock 《Bioorganic & medicinal chemistry letters》2013,23(16):4674-4679
The structure activity relationship of the prime region of conformationally restricted hydroxyethylamine (HEA) BACE inhibitors is described. Variation of the P1′ region provided selectivity over Cat-D with a series of 2,2-dioxo-isothiochromanes and optimization of the P2′ substituent of chromane–HEA(s) with polar substituents provided improvements in the compound’s in vitro permeability. Significant potency gains were observed with small aliphatic substituents such as methyl, n-propyl, and cyclopropyl when placed at the C-2 position of the chromane. 相似文献
5.
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
6.
Laras Y Garino C Dessolin J Weck C Moret V Rolland A Kraus JL 《Journal of enzyme inhibition and medicinal chemistry》2009,24(1):181-187
Synthesis and enzymatic evaluation of new series of N(4)-substituted piperazine naphthamide derivatives as BACE-1 inhibitors for the treatment of Alzheimer's disease are reported. 相似文献
7.
Neuropeptide FF (NPFF) has been shown to act as an endogenous anti-analgesic peptide. In this paper, several peptide analogs of the selective ligand dNP(NMe)AFLFQPQRF-NH(2) modified in the putative address segment, were designed to be selective NPFF(2) receptor probes, synthesized and assayed. One peptide dA(NMe)AAFLFQPQRF-NH(2) displays a very high affinity for NPFF(2) receptors transfected in CHO cells, and a high selectivity versus NPFF(1) receptors. The exact residues carried in the N-terminal part of the ligands are not decisive to obtain a high affinity only the length of the peptide in itself seems important to create selectivity. 相似文献
8.
ABSTRACT: BACKGROUND: The inhibition of the activity of beta-secretase (BACE-1) is a potentially important approach for the treatment of Alzheimer disease. To explore the mechanism of inhibition, we describe the use of 46 X-ray crystallographic BACE-1/inhibitor complexes to derive quantitative structure-activity relationship (QSAR) models. The inhibitors were aligned by superimposing 46 X-ray crystallographic BACE-1/inhibitor complexes, and gCOMBINE software was used to perform COMparative BINding Energy (COMBINE) analysis on these 46 minimized BACE-1/inhibitor complexes. The major advantage of the COMBINE analysis is that it can quantitatively extract key residues involved in binding the ligand and identify the nature of the interactions between the ligand and receptor. RESULTS: By considering the contributions of the protein residues to the electrostatic and van der Waals intermolecular interaction energies, two predictive and robust COMBINE models were developed: (i) the 3-PC distance-dependent dielectric constant model (built from a single X-ray crystal structure) with a q2 value of 0.74 and an SDEC value of 0.521; and (ii) the 5-PC sigmoidal electrostatic model (built from the actual complexes present in the Brookhaven Protein Data Bank) with a q2 value of 0.79 and an SDEC value of 0.41. CONCLUSIONS: These QSAR models and the information describing the inhibition provide useful insights into the design of novel inhibitors via the optimization of the interactions between ligands and those key residues of BACE-1. 相似文献
9.
McGaughey GB Colussi D Graham SL Lai MT Munshi SK Nantermet PG Pietrak B Rajapakse HA Selnick HG Stauffer SR Holloway MK 《Bioorganic & medicinal chemistry letters》2007,17(4):1117-1121
BACE-1 is a flexible enzyme with experimentally determined motion in the flap region, the catalytic aspartates, and the 10s loop. Four in-house crystallographically determined complexes of tertiary carbinamine inhibitors revealed 10s loop motion in the S(3) pocket. These X-ray structures were used to correlate K(i) values, which span over five orders of magnitude, with the calculated interaction energy, using the Merck Molecular Force Field for a series of 19 tertiary carbinamine inhibitors. 相似文献
10.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(1):153-162
We report the synthesis and the β-site amyloid precursor protein cleaving enzyme-1 inhibitory properties of novel phenyl(thio)ureas bearing 2-(thio)oxothiazoline derivatives. A library of analogues was prepared according to specific synthetic schemes and the inhibitory activity was monitored using a fluorescence resonance energy transfer assay. Several analogues show potent inhibitory activities ranging between 1 and 0.01 µM and the activity is related to the NH acidity of the (thio)urea motif. Our results illustrate once again the close relationship between molecular recognition, complexation of the active site in enzymatic system, and organocatalysis utilizing explicit hydrogen bonding. 相似文献
11.
Rueeger H Rondeau JM McCarthy C Möbitz H Tintelnot-Blomley M Neumann U Desrayaud S 《Bioorganic & medicinal chemistry letters》2011,21(7):1942-1947
This Letter describes the de novo design of non-peptidic hydroxyethylamine (HEA) inhibitors of BACE-1 by elimination of P-gp contributing amide attachments. The predicted binding mode of the novel cyclic sulfone HEA core template was confirmed in a X-ray co-crystal structure. Inhibitors of sub-micromolar potency with an improved property profile over historic HEA inhibitors resulting in improved brain penetration are described. 相似文献
12.
《Carbohydrate research》1999,315(1-2):106-116
The C-glucosyl aldehyde, 2-C-(2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl)ethanal was prepared from the C-glucopyranosyl propene precursor by ozonolysis. Reductive amination of the C-glucosyl aldehyde and subsequent deprotection gave 1-anilino-2-C-(α-d-glucopyranosyl)ethane. The E and Z isomers of the oxime derivative, 1-C-(α-d-arabinofuranosyl)methanal oxime were prepared by treating their aldehyde precursor with hydroxylamine. Acetylation of the oxime, followed by catalytic hydrogenation and deprotection, gave the corresponding 1-C-(α-d-arabinofuranosyl)methylamine. Reductive amination of ethyl 2,3-O-isopropylidene-α-d-lyxo-pentodialdo-1,4-furanoside using aniline gave ethyl 5-anilino-5-deoxy-d-lyxo-furanoside. Inhibition studies with these compounds on β-d-glucosidase from sweet almond, using o-nitrophenyl d-glucopyranoside as substrate, were carried out. 相似文献
13.
Kumar AB Anderson JM Melendez AL Manetsch R 《Bioorganic & medicinal chemistry letters》2012,22(14):4740-4744
A library of 1,3-disubstituted 2-propanols was synthesized and evaluated as low molecular weight probes for β-secretase inhibition. By screening a library of 121 1,3-disubstituted 2-propanol derivatives, we identified few compounds inhibiting the enzyme at low micromolar concentrations. The initial hits were optimized to yield a potent BACE-1 inhibitor exhibiting an IC(50) constant in the nanomolar range. Exploration of the pharmacological properties revealed that these small molecular inhibitors possessed a high selectivity over cathepsin D and desirable physicochemical properties beneficial to cross the blood-brain barrier. 相似文献
14.
Coburn CA Stachel SJ Jones KG Steele TG Rush DM DiMuzio J Pietrak BL Lai MT Huang Q Lineberger J Jin L Munshi S Katharine Holloway M Espeseth A Simon A Hazuda D Graham SL Vacca JP 《Bioorganic & medicinal chemistry letters》2006,16(14):3635-3638
A series of beta-site amyloid precursor protein cleaving enzyme (BACE-1) inhibitors containing a psi(CH2NH) reduced amide bond were synthesized. Incorporation of this reduced amide isostere as a non-cleavable peptide surrogate afforded inhibitors possessing low nanomolar potencies in both an enzymatic and cell-based assay. 相似文献
15.
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
16.
Bahudhanapati H Zhang Y Sidhu SS Brew K 《The Journal of biological chemistry》2011,286(36):31761-31770
Tissue inhibitor of metalloproteinases-2 (TIMP-2) is a broad spectrum inhibitor of the matrix metalloproteinases (MMPs), which function in extracellular matrix catabolism. Here, phage display was used to identify variants of human TIMP-2 that are selective inhibitors of human MMP-1, a collagenase whose unregulated action is linked to cancer, arthritis, and fibrosis. Using hard randomization of residues 2, 4, 5, and 6 (L1) and soft randomization of residues 34-40 (L2) and 67-70 (L3), a library was generated containing 2 × 10(10) variants of TIMP-2. Five clones were isolated after five rounds of selection with MMP-1, using MMP-3 as a competitor. The enriched phages selectively bound MMP-1 relative to MMP-3 and contained mutations only in L1. The most selective variant (TM8) was used to generate a second library in which residues Cys(1)-Gln(9) were soft-randomized. Four additional clones, selected from this library, showed a similar affinity for MMP-1 as wild-type TIMP-2 but reduced affinity for MMP-3. Variants of the N-terminal domain of TIMP-2 (N-TIMP-2) with the sequences of the most selective clones were expressed and characterized for inhibitory activity against eight MMPs. All were effective inhibitors of MMP-1 with nanomolar K(i) values, but TM8, containing Ser(2) to Asp and Ser(4) to Ala substitutions, was the most selective having a nanomolar K(i) value for MMP-1 but no detectable inhibitory activity toward MMP-3 and MMP-14 up to 10 μM. This study suggests that phage display and selection with other MMPs may be an effective method for discovering tissue inhibitor of metalloproteinase variants that discriminate between specified MMPs as targets. 相似文献
17.
18.
Lindsley SR Moore KP Rajapakse HA Selnick HG Young MB Zhu H Munshi S Kuo L McGaughey GB Colussi D Crouthamel MC Lai MT Pietrak B Price EA Sankaranarayanan S Simon AJ Seabrook GR Hazuda DJ Pudvah NT Hochman JH Graham SL Vacca JP Nantermet PG 《Bioorganic & medicinal chemistry letters》2007,17(14):4057-4061
This Letter describes the design and synthesis of tertiary carbinamine macrocyclic inhibitors of the beta-secretase (BACE-1) enzyme. These macrocyclic inhibitors, some of which incorporate novel P2 substituents, display a 2- to 100-fold increase in potency relative to the previously described acyclic analogs while affording greater stability. 相似文献
19.
Park H Min K Kwak HS Koo KD Lim D Seo SW Choi JU Platt B Choi DY 《Bioorganic & medicinal chemistry letters》2008,18(9):2900-2904
We describe synthesis and evaluation of a series of cyclic urea derivatives with hydroxylethylamine isostere. Modification of P3, P1, and P2′ and combination of SAR display a >100-fold increase in potency with good cellular activity (IC50 = 0.15 μM) relative to the previously reported compound 3. 相似文献
20.
Christian Sund Oscar Belda Neera Borkakoti Jimmy Lindberg Dean Derbyshire Lotta Vrang Elizabeth Hamelink Cathrine Åhgren Esmeralda Woestenenk Kristina Wikström Anders Eneroth Erik Lindström Genadiy Kalayanov 《Bioorganic & medicinal chemistry letters》2012,22(21):6721-6727
A set of low molecular weight compounds containing a hydroxyethylamine (HEA) core structure with different prime side alkyl substituted 4,5,6,7-tetrahydrobenzazoles and one 4,5,6,7-tetrahydropyridinoazole was synthesized. Striking differences were observed on potencies in the BACE-1 enzymatic and cellular assays depending on the nature of the heteroatoms in the bicyclic ring, from the low active compound 4 to inhibitor 6, displaying BACE-1 IC50 values of 44 nM (enzyme assay) and 65 nM (cell-based assay). 相似文献