共查询到20条相似文献,搜索用时 15 毫秒
1.
KMI-358 and KMI-370, highly potent and small-sized BACE1 inhibitors containing phenylnorstatine 总被引:3,自引:0,他引:3
Kimura T Shuto D Kasai S Liu P Hidaka K Hamada T Hayashi Y Hattori C Asai M Kitazume S Saido TC Ishiura S Kiso Y 《Bioorganic & medicinal chemistry letters》2004,14(6):1527-1531
Recently, we reported a novel substrate-based octapeptide BACE1 inhibitor KMI-008 containing hydroxymethylcarbonyl (HMC) isostere as a transition-state mimic. Using KMI-008 as a lead compound, a small-sized and highly potent BACE1 inhibitor KMI-370 (IC(50)=3.4 nM) was designed and synthesized. 相似文献
2.
Kenji Suzuki Yoshio Hamada Jeffrey-Tri Nguyen Yoshiaki Kiso 《Bioorganic & medicinal chemistry》2013,21(21):6665-6673
We have reported potent peptidic and non-peptidic BACE1 inhibitors with a hydroxymethylcarbonyl (HMC) isostere as a substrate transition-state mimic. However, our potent inhibitors possess a tetrazole ring at the P1′ position. It is desirable that central nervous system (CNS) drugs do not possess an acidic moiety. In this study, we synthesized non-acidic BACE1 inhibitors with heterocyclic derivatives at the P1′ position. KMI-1764 (27) exhibited potent inhibitory activity (IC50 = 27 nM). Interestingly, these non-acidic inhibitors tended to follow the quantitative structure–activity relationship (QSAR) equation and interacted with BACE1-Arg235 in the binding model. 相似文献
3.
Bertini S Asso V Ghilardi E Granchi C Manera C Minutolo F Saccomanni G Bortolato A Mason J Moro S Macchia M 《Bioorganic & medicinal chemistry letters》2011,21(22):6657-6661
β-Secretase (BACE1) is widely recognized as a prime drug target for the treatment of Alzheimer's disease (AD). In this Letter, we report the synthesis and the BACE1 inhibitory activity of novel, variously substituted N-[3-(9H-carbazol-9-yl)-2-hydroxypropyl]-arylcarboxamides. The best results have been obtained with the introduction of a 4-OMe substituent (IC(50)=3.8 μM) or a 3,4-dichloro substituent (IC(50)=2.5 μM) in the amidic aromatic ring. The blood-brain barrier penetration predictions resulted to be promising for this type of compounds. To better understand the structure-activity relationships (SAR) of the new derivatives, a docking study procedure has been applied exploiting different conformational and ionic states of BACE1. 相似文献
4.
James Madden Jenny R. Dod Robert Godemann Joachim Kraemer Myron Smith Marion Biniszkiewicz David J. Hallett John Barker Jane D. Dyekjaer Thomas Hesterkamp 《Bioorganic & medicinal chemistry letters》2010,20(17):5329-5333
A novel series of 2-aminobenzimidazole inhibitors of BACE1 has been discovered using fragment-based drug discovery (FBDD) techniques. The rapid optimization of these inhibitors using structure-guided medicinal chemistry is discussed. 相似文献
5.
Thiophene substituted acylguanidines as BACE1 inhibitors 总被引:1,自引:0,他引:1
Fobare WF Solvibile WR Robichaud AJ Malamas MS Manas E Turner J Hu Y Wagner E Chopra R Cowling R Jin G Bard J 《Bioorganic & medicinal chemistry letters》2007,17(19):5353-5356
A series of thiophene-substituted acylguanidines were designed from a pyrrole substituted acylguanidine HTS lead. This template allowed a greater flexibility, through differential Suzuki couplings, to explore the binding site of BACE1 and to enhance the inhibitory potencies. This exploration provided a 25-fold enhancement in potency to yield compound 10a, which was 150 nM in a BACE1 FRET assay. 相似文献
6.
《Bioorganic & medicinal chemistry letters》2014,24(23):5455-5459
The synthesis of a series of iminoheterocycles and their structure–activity relationships (SAR) as inhibitors of the aspartyl protease BACE1 will be detailed. An effort to access the S3 subsite directly from the S1 subsite initially yielded compounds with sub-micromolar potency. A subset of compounds from this effort unexpectedly occupied a different binding site and displayed excellent BACE1 affinities. Select compounds from this subset acutely lowered Aβ40 levels upon subcutaneous and oral administration to rats. 相似文献
7.
Sorribas A Jiménez JI Yoshida WY Williams PG 《Bioorganic & medicinal chemistry》2011,19(22):6581-6586
Bioassay-guided fractionation of an extract prepared from the fruiting bodies of a Daedalea sp. has led to the isolation of daedalols A-C (1-3). The structures of these new triterpenes were elucidated based on extensive NMR spectroscopic and mass spectrometric measurements. Assignment of the relative configuration of 3 required the preparation of a suitable derivative via a Payne rearrangement. The aspartic protease BACE1, an Alzheimer's drug target, was inhibited by 3 with an IC(50) value of 14.2 μM. 相似文献
8.
Hamada Y Nakanishi T Suzuki K Yamaguchi R Hamada T Hidaka K Ishiura S Kiso Y 《Bioorganic & medicinal chemistry letters》2012,22(14):4640-4644
Recently, we reported substrate-based pentapeptidic BACE1 inhibitors possessing a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. These inhibitors showed potent inhibitory activities in enzymatic and cell assays. We also designed and synthesized non-peptidic and small-sized inhibitors possessing a heterocyclic scaffold at the P(2) position. By studying the structure-activity relationship of these inhibitors, we found that the σ-π interaction of an inhibitor with the BACE1-Arg235 side chain played a key role in the inhibition mechanism. Hence, we optimized the inhibitors with a focus on their P(2) regions. In this Letter, a series of novel BACE1 inhibitors possessing a 5-nitroisophthalic scaffold at the P(2) position are described along with the results of the related structure-activity relationship study. These small-sized inhibitors are expected improved membrane permeability and bioavailability. 相似文献
9.
The development of potent non-peptidic PTP-1B inhibitors 总被引:2,自引:0,他引:2
Dufresne C Roy P Wang Z Asante-Appiah E Cromlish W Boie Y Forghani F Desmarais S Wang Q Skorey K Waddleton D Ramachandran C Kennedy BP Xu L Gordon R Chan CC Leblanc Y 《Bioorganic & medicinal chemistry letters》2004,14(4):1039-1042
The SAR from our peptide libraries was exploited to design a series of potent deoxybenzoin PTP-1B inhibitors. The introduction of an ortho bromo substituent next to the difluoromethylphosphonate warhead gave up to 20-fold increase in potency compared to the desbromo analogues. In addition, these compounds were orally bioavailable and active in the animal models of non-insulin dependent diabetes mellitus (NIDDM). 相似文献
10.
Simone Bertini Elisa Ghilardi Valentina Asso Filippo Minutolo Simona Rapposelli Maria Digiacomo Giuseppe Saccomanni Veronica Salmaso Mattia Sturlese Stefano Moro Marco Macchia Clementina Manera 《Bioorganic & medicinal chemistry letters》2017,27(21):4812-4816
A novel series of variously substituted N-[3-(9H-carbazol-9-yl)-2-hydroxypropyl]-arylsulfonamides has been synthesized and assayed for β-Secretase (BACE1) inhibitory activity. BACE1 is a widely recognized drug target for the prevention and treatment of Alzheimer's Disease (AD). The introduction of benzyl substituents on the nitrogen atom of the arylsulfonamide moiety has so far led to the best results, with three derivatives showing IC50 values ranging from 1.6 to 1.9?μM. Therefore, a significant improvement over the previously reported series of N-carboxamides (displaying IC50’s?≥?2.5?μM) has been achieved, thus suggesting an active role of the sulfonamido-portion in the inhibition process. Preliminary molecular modeling studies have been carried out to rationalize the observed structure-activity relationships. 相似文献
11.
Ping Zhou Yanfang Li Yi Fan Zheng Wang Rajiv Chopra Andrea Olland Yun Hu Ronald L. Magolda Menelas Pangalos Peter H. Reinhart M. James Turner Jonathan Bard Michael S. Malamas Albert J. Robichaud 《Bioorganic & medicinal chemistry letters》2010,20(7):2326-2329
A novel class of pyridinyl aminohydantoins was designed and prepared as highly potent BACE1 inhibitors. Compound (S)-4g showed excellent potency with IC50 of 20 nM for BACE1. X-ray crystallography indicated that the interaction between pyridine nitrogen and the tryptophan Trp76 was a key feature in the S2′ region of the enzyme that contributed to increased potency. 相似文献
12.
《Bioorganic & medicinal chemistry letters》2014,24(9):2033-2045
Beta site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors hold great potential as disease modifying anti-Alzheimer’s drugs. This digest provides an overview of the amidine containing class of BACE1 inhibitors, of which multiple examples are now progressing through clinical trials. The various structural modifications highlight the struggle to combine potency with the optimal properties for a brain penetrant BACE1 inhibitor, and illustrate the crowded competitive landscape. This overview concludes with a summary of potential issues including substrate and target selectivity and a synopsis of the status of the current and past clinical assets. 相似文献
13.
Bioassay-guided fractionation of an extract prepared from the fruits of Cordia sebestena led to the isolation of sebestenoids A-D (1-4). Their structures were elucidated on the basis of extensive NMR experiments and mass spectroscopic measurements. Compounds 1-4 exhibited moderate inhibition of the aspartic protease BACE1. 相似文献
14.
Navya?Raj Agnes?Helen N.?Manoj G.?Harish Vipin?Thomas Shailja?Singh Seema?Sehrawat Shaguna?Seth Achuthsankar?S.?Nair Abhinav?Grover Pawan?K.?Dhar
Peptides are increasingly used as inhibitors of various disease specific targets. Several naturally occurring and synthetically developed peptides are undergoing clinical trials. Our work explores the possibility of reusing the non-expressing DNA sequences to predict potential drug-target specific peptides. Recently, we experimentally demonstrated the artificial synthesis of novel proteins from non-coding regions of Escherichia coli genome. In this study, a library of synthetic peptides (Synpeps) was constructed from 2500 intergenic E. coli sequences and screened against Beta-secretase 1 protein, a known drug target for Alzheimer’s disease (AD). Secondary and tertiary protein structure predictions followed by protein–protein docking studies were performed to identify the most promising enzyme inhibitors. Interacting residues and favorable binding poses of lead peptide inhibitors were studied. Though initial results are encouraging, experimental validation is required in future to develop efficient target specific inhibitors against AD. 相似文献
15.
Hu B Fan KY Bridges K Chopra R Lovering F Cole D Zhou P Ellingboe J Jin G Cowling R Bard J 《Bioorganic & medicinal chemistry letters》2004,14(13):3457-3460
A new series of bis-statine based peptidomimetic inhibitors of human beta-secretase (BACE 1) was developed by structure-based modification of the three regions to the initial lead 3: an N-terminus, a central bis-statine core, and a C-terminus. Introduction of a 4-aminomethylbenzoic acid on the C-terminus resulted in a potent BACE 1 inhibitor with an IC50 value of 21 nM. The general requirements for the optimal substrate-enzyme interaction are disclosed herein. 相似文献
16.
Kortum SW Benson TE Bienkowski MJ Emmons TL Prince DB Paddock DJ Tomasselli AG Moon JB LaBorde A TenBrink RE 《Bioorganic & medicinal chemistry letters》2007,17(12):3378-3383
The design and synthesis of a novel series of potent BACE1 hydroxyethylamine inhibitors. These inhibitors feature hydrogen bonding substituents at the C-5 position of the isophthalamide ring with improved selectivity over cathepsin D. 相似文献
17.
Ying-zi Xu Shendong Yuan Simeon Bowers Roy K. Hom Wayman Chan Hing L. Sham Yong L. Zhu Paul Beroza Hu Pan Eric Brecht Nanhua Yao Julie Lougheed Jiangli Yan Danny Tam Zhao Ren Lany Ruslim Michael P. Bova Dean R. Artis 《Bioorganic & medicinal chemistry letters》2013,23(10):3075-3080
Utilizing a structure based design approach, combined with extensive medicinal chemistry execution, highly selective, potent and novel BACE1 inhibitor 8 (BACE1 Alpha assay IC50 = 8 nM) was made from a weak μM potency hit in an extremely efficient way. The detailed SAR and general design approaches will be discussed. 相似文献
18.
Hamada Y Tagad HD Nishimura Y Ishiura S Kiso Y 《Bioorganic & medicinal chemistry letters》2012,22(2):1130-1135
Previously reported pentapeptidic BACE1 inhibitors, designed using a substrate-based approach, were used as lead compounds for the further design of non-peptidic BACE1 inhibitors. Although these peptidic and non-peptidic inhibitors, with a hydroxymethylcarbonyl isostere as a substrate transition-state mimic, exhibited potent BACE1 inhibitory activities, their molecular-sizes appeared a little too big (molecular weight of >600daltons) for developing practical anti-Alzheimer's disease drugs. To develop lower weight BACE1 inhibitors, a series of tripeptidic BACE1 inhibitors were devised using a design approach based on the conformation of a virtual inhibitor bound to the BACE1 active site, also called 'in-silico conformational structure-based design'. Although these tripeptidic BACE1 inhibitors contained some natural amino acid residues, they are expected to be useful as lead compounds for developing the next generation BACE1 inhibitors, due to their low molecular size and unique structural features compared with previously reported inhibitors. 相似文献
19.
Holsworth DD Powell NA Downing DM Cai C Cody WL Ryan JM Ostroski R Jalaie M Bryant JW Edmunds JJ 《Bioorganic & medicinal chemistry》2005,13(7):2657-2664
Ketopiperazine 2 was designed from a previously published analog. Compound 2 was shown to be a novel, potent inhibitor of renin that, when administered orally, lowered blood pressure in a hypertensive double transgenic (human renin and angiotensinogen) mouse model. Compound 2 was further optimized to sub-nanomolar potency by designing an analog that addressed the S3 sub-pocket of the renin enzyme (16). 相似文献
20.
《Bioorganic & medicinal chemistry letters》2014,24(17):4141-4150
We discovered a novel series of non-peptidic acylguanidine inhibitors of Cathepsin D as target for osteoarthritis. The initial HTS-hits were optimized by structure-based design using CatD X-ray structures resulting in single digit nanomolar potency in the biochemical CatD assay. However, the most potent analogues showed only micromolar activities in an ex vivo glycosaminoglycan (GAG) release assay in bovine cartilage together with low cellular permeability and suboptimal microsomal stability. This new scaffold can serve as a starting point for further optimization towards in vivo efficacy. 相似文献