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1.
P3 cap modified Phe*-Ala series BACE inhibitors 总被引:1,自引:0,他引:1
Chen SH Lamar J Guo D Kohn T Yang HC McGee J Timm D Erickson J Yip Y May P McCarthy J 《Bioorganic & medicinal chemistry letters》2004,14(1):245-250
With the aim of reducing molecular weight and adjusting log D value of BACE inhibitors to more favorable range for BBB penetration and better bioavailability, we synthesized and evaluated several series of P3 cap modified BACE inhibitors obtained via replacement of the P3NHBoc moiety as seen in 3 with other polar functional groups such as amino, hydroxyl and fluorine. Several promising inhibitors emerging from this P3 cap SAR study (e.g., 15 and 19) demonstrated good enzyme inhibitory potencies (BACE-1 IC(50) <50 nM) and whole cell activities (IC(50) approximately 1 microM). 相似文献
2.
Hong Zhu Mary B. Young Philippe G. Nantermet Samuel L. Graham Dennis Colussi Ming-Tain Lai Beth Pietrak Eric A. Price Sethu Sankaranarayanan Xiao-ping Shi Katherine Tugusheva Marie A. Holahan Maria S. Michener Jacquelynn J. Cook Adam Simon Daria J. Hazuda Joseph P. Vacca Hemaka A. Rajapakse 《Bioorganic & medicinal chemistry letters》2010,20(5):1779-1782
This Letter describes the one pot synthesis of tertiary carbinamine 3 and related analogs of brain penetrant BACE-1 inhibitors via the alkylation of the Schiff base intermediate 2. The methodology developed for this study provided a convenient and rapid means to explore the P1 region of these types of inhibitors, where the P1 group is installed in the final step using a one-pot two-step protocol. Further SAR studies led to the identification of 10 which is twofold more potent in vitro as compared to the lead compound. This inhibitor was characterized in a cisterna magna ported rhesus monkey model, where significant lowering of CSF Aβ40 was observed. 相似文献
3.
Donkor IO Korukonda R Huang TL LeCour L 《Bioorganic & medicinal chemistry letters》2003,13(5):783-784
Four new peptidyl aldehydes bearing proline mimetics at the P(2)-position were synthesized and studied as inhibitors of calpain I, cathepsin B, and selected serine proteases. The ring size of the P(2)-constraining residue influenced the inhibitory potency and selectivity of the compounds for calpain I compared to the other proteases. 相似文献
4.
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
5.
Yong-Jin Wu Yunhui Zhang Andrew C. Good Catherine R. Burton Jeremy H. Toyn Charles F. Albright John E. Macor Lorin A. Thompson 《Bioorganic & medicinal chemistry letters》2009,19(10):2654-2660
A series of N-((2S,3R)-1-(3,5-difluorophenyl)-3-hydroxy-4-(3-methoxybenzylamino)-butan-2-yl)benzamides has been synthesized as BACE inhibitors. A variety of P2 and P3 substituents has been explored, and these efforts have culminated in the identification of several 1,3,5-trisubstituted phenylcarboxyamides with potent BACE inhibitory activity. 相似文献
6.
Boros EE Deaton DN Hassell AM McFadyen RB Miller AB Miller LR Paulick MG Shewchuk LM Thompson JB Willard DH Wright LL 《Bioorganic & medicinal chemistry letters》2004,14(13):3425-3429
The synthesis and biological activity of a series of aldehyde inhibitors of cathepsin K are reported. Exploration of the properties of the S2 and S3 subsites with a series of carbamate derivatized norleucine aldehydes substituted at the P2 and P3 positions afforded analogs with cathepsin K IC50s between 600 nM and 130 pM. 相似文献
7.
Wang Y Huang JC Zhou ZL Yang W Guastella J Drewe J Cai SX 《Bioorganic & medicinal chemistry letters》2004,14(5):1269-1272
This article describes the synthesis and biological evaluation of a series of dipeptidyl aspartyl fluoromethylketones as caspase-3 inhibitors. Structure-activity relationship (SAR) studies showed that for caspase-3 inhibition, Val is the best P(2) amino acid. The SAR studies also showed that the Asp free carboxylic acid in P(1) is important for caspase inhibiting activities, as well as for selectivity over other proteases. 相似文献
8.
Zhou Y Gregor VE Ayida BK Winters GC Sun Z Murphy D Haley G Bailey D Froelich JM Fish S Webber SE Hermann T Wall D 《Bioorganic & medicinal chemistry letters》2007,17(5):1206-1210
Aminoglycoside antibiotics target an internal RNA loop within the bacterial ribosomal decoding site. Here, we describe the synthesis and SAR of novel 3,5-diamino-piperidine derivatives as aminoglycoside mimetics, and show they act as inhibitors of bacterial translation and growth. 相似文献
9.
《Bioorganic & medicinal chemistry letters》2014,24(11):2521-2524
This Letter describes the further development and SAR exploration of a novel series of Legumain inhibitors. Based upon a previously identified Legumain inhibitor from our group, we explored the SAR of the carbamate phenyl ring system to probe the P3 pocket of the enzyme. This led to the identification of a sub-nanomolar inhibitor of Legumain. 相似文献
10.
Kranjc A Peterlin-Masic L Ilas J Prezelj A Stegnar M Kikelj D 《Bioorganic & medicinal chemistry letters》2004,14(12):3251-3256
Optimization of lead compounds 1 and 2 resulted in novel, selective, and potent thrombin inhibitors incorporating weakly basic heterobicyclic P(1)-arginine mimetics. The design, synthesis, and biological activity of racemic thrombin inhibitors 17-29 and enantiomerically pure thrombin inhibitors 30-33 are described. The arginine side-chain mimetics used in this study are 4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine, 4,5,6,7-tetrahydro-2H-indazole, and 2-imino-4,5,6,7-tetrahydro-1,3-benzothiazol-3(2H)-ylamine. 相似文献
11.
Peterlin-Masic L Kranjc A Marinko P Mlinsek G Solmajer T Stegnar M Kikelj D 《Bioorganic & medicinal chemistry letters》2003,13(19):3171-3176
Novel, highly selective and potent thrombin inhibitors were identified as a result of combing the 3-benzylsulfonylamino-2-pyridinone acetamide P(2)-P(3) surrogate with weakly basic partially saturated heterobicyclic P(1)-arginine mimetics 1-8. The design, synthesis, biological activity, and the binding modes of non-covalent thrombin inhibitors featuring P(1)-4,5,6,7-tetrahydroindazole, 5,6,7,8-tetrahydroquinazoline, and 4,5,6,7-tetrahydrobenzothiazole moieties are described. 相似文献
12.
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
13.
Kazmierski WM Furfine E Spaltenstein A Wright LL 《Bioorganic & medicinal chemistry letters》2002,12(23):3431-3433
We have developed concise and efficient syntheses of novel spirocyclic pyrrolidones 1-3, which involve the alkylation of pyrrolidone precursor 13 with 1,5-dibromopentane, 16 and 15, followed by an in situ lactamization. Conjugates of 1 and 2 with P1'/P2' hydroxy-indanolamine moiety resulted in novel and potent inhibitors of HIV-1 protease 25 and 26, suggesting that 1 and 2 are novel P2/P1 HIV-PI mimetics. 相似文献
14.
Yoshio Hamada Hiroko Ohta Naoko Miyamoto Diganta Sarma Takashi Hamada Tomoya Nakanishi Moe Yamasaki Abdellah Yamani Shoichi Ishiura Yoshiaki Kiso 《Bioorganic & medicinal chemistry letters》2009,19(9):2435-2439
Recently, we reported potent substrate-based pentapeptidic BACE1 inhibitors possessing a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. Because these inhibitors contained some natural amino acids, we would need to improve their enzymatic stability in vivo and permeability across the blood–brain barrier, so that they become practically useful. Subsequently, non-peptidic and small-sized BACE1 inhibitors possessing a heterocyclic scaffold, 2,6-pyridenedicarboxylic, chelidamic or chelidonic moiety, at the P2 position were reported. These inhibitors were designed based on the conformer of docked inhibitor in BACE1. In this study, we discuss the role and significance of interactions between Arg235 of BACE1 and its inhibitor in BACE1 inhibitory mechanism. Moreover, we designed more potent small-sized BACE1 inhibitors with a 2,6-pyridinedicarboxylic scaffold at the P2 position, that were optimized for the interactions with Arg235 of BACE1. 相似文献
15.
Amantullah Ansari Sharad Satalkar Varshavekumar Patil Amit S. Shete Simranjeet Kaur Ashu Gupta Siddhartha Singh Mohd. Raja Daniel L. Severance Sebastián Bernales Sarvajit Chakravarty David T. Hung Son M. Pham Francisco J. Herrera Roopa Rai 《Bioorganic & medicinal chemistry letters》2017,27(2):217-222
EZH2 (enhancer of zeste homologue 2) is the catalytic subunit of the polycomb repressive complex 2 (PRC2) that catalyzes the methylation of lysine 27 of histone H3 (H3K27). Dysregulation of EZH2 activity is associated with several human cancers and therefore EZH2 inhibition has emerged as a promising therapeutic target. Several small molecule EZH2 inhibitors with different chemotypes have been reported in the literature, many of which use a bicyclic heteroaryl core. Herein, we report the design and synthesis of EZH2 inhibitors containing an indoline core. Partial saturation of an indole to an indoline provided lead compounds with nanomolar activity against EZH2, while also improving solubility and oxidative metabolic stability. 相似文献
16.
John J.M. Wiener Alvah T. Wickboldt Danielle K. Wiener Alice Lee-Dutra James P. Edwards Lars Karlsson Steven Nguyen Siquan Sun Todd K. Jones Cheryl A. Grice 《Bioorganic & medicinal chemistry letters》2010,20(7):2375-2378
A novel class of tetrahydropyrido-pyrazole thioether amines that display potency against human Cathepsin S have been previously reported. Here, further SAR investigations of the P3, P4, and P5 regions are described. In particular, 4-fluoropiperidine is identified as a competent P3 binding element when utilized in conjunction with a (S)-2-hydroxypropyl linker-containing P5 moiety and oxamide or sulfonamide P4 substitution. 相似文献
17.
Tully DC Liu H Chatterjee AK Alper PB Epple R Williams JA Roberts MJ Woodmansee DH Masick BT Tumanut C Li J Spraggon G Hornsby M Chang J Tuntland T Hollenbeck T Gordon P Harris JL Karanewsky DS 《Bioorganic & medicinal chemistry letters》2006,16(19):5112-5117
The synthesis and structure-activity relationship of a series of arylaminoethyl amide cathepsin S inhibitors are reported. Optimization of P3 and P2 groups to improve overall physicochemical properties resulted in significant improvements in oral bioavailability over early lead compounds. An X-ray structure of compound 37 bound to the active site of cathepsin S is also reported. 相似文献
18.
Hemaka A. Rajapakse Philippe G. Nantermet Harold G. Selnick James C. Barrow Georgia B. McGaughey Sanjeev Munshi Stacey R. Lindsley Mary Beth Young Phung L. Ngo M. Katherine Holloway Ming-Tain Lai Amy S. Espeseth Xiao-Ping Shi Dennis Colussi Beth Pietrak Ming-Chih Crouthamel Katherine Tugusheva Qian Huang Min Xu Adam J. Simon Joseph P. Vacca 《Bioorganic & medicinal chemistry letters》2010,20(6):1885-1889
The optimization of tertiary carbinamine derived inhibitors of BACE1 from its discovery as an unstable lead to low nanomolar cell active compounds is described. Five-membered heterocycles are reported as stable and potency enhancing linkers. In the course of this work, we have discovered a clear trend where the activity of inhibitors at a given assay pH is dependent on pKa of the amino group that interacts directly with the catalytic aspartates. The potency of compounds as inhibitors of Αβ production in a cell culture assay correlated much better with BACE1 enzyme potency measured at pH 7.5 than at pH 4.5. 相似文献
19.
Dahlgren A Brånalt J Kvarnström I Nilsson I Musil D Samuelsson B 《Bioorganic & medicinal chemistry》2002,10(5):1567-1580
With the objective to prepare novel non-peptidic thrombin inhibitors, bioisosteres of the inhibitory tripeptide D-Phe-Pro-Arg chain have been examined. Thus, the P1 Arg was replaced with p-amidinobenzylamine, an elongated homologue of the same and with 2,5-dichloro benzylamine. The P2-P3, D-Phe-Pro, was replaced with a novel tartaric acid template coupled to a series of readily available, mainly lipophilic, amines. Some of these compounds exhibit promising thrombin inhibition activity in vitro, IC(50 ) approximately 5.9 microM. 相似文献
20.
Hamada Y Abdel-Rahman H Yamani A Nguyen JT Stochaj M Hidaka K Kimura T Hayashi Y Saito K Ishiura S Kiso Y 《Bioorganic & medicinal chemistry letters》2008,18(5):1649-1653
Recently, we reported potent BACE1 inhibitors KMI-429, -684, and -574 possessing a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. These inhibitors showed potent inhibitory activities in enzymatic and cell assays, especially, KMI-429 was confirmed to significantly inhibit Abeta production in vivo. However, acidic moieties at the P(4) and P(1)' positions of KMI-compounds were thought to be unfavorable for membrane permeability across the blood-brain barrier. Herein, we replaced acidic moieties at the P(4) position with other hydrogen bond acceptor groups, and these inhibitors exhibited improved BACE1 inhibitory activities in cultured cells. In this study, we replaced the acidic moieties at the P(1)' position with non-acidic and low molecular sized moieties. 相似文献