共查询到20条相似文献,搜索用时 15 毫秒
1.
Fischer C Zultanski SL Zhou H Methot JL Brown WC Mampreian DM Schell AJ Shah S Nuthall H Hughes BL Smotrov N Kenific CM Cruz JC Walker D Bouthillette M Nikov GN Savage DF Jeliazkova-Mecheva VV Diaz D Szewczak AA Bays N Middleton RE Munoz B Shearman MS 《Bioorganic & medicinal chemistry letters》2011,21(13):4083-4087
Synthesis, SAR, and evaluation of aryl triazoles as novel gamma secretase modulators (GSMs) are presented in this communication. Starting from the literature and in-house leads, we evaluated a range of five-membered heterocycles as replacements for olefins commonly found in non-acid GSMs. 1,2,3-C-aryl-triazoles were identified as suitable replacements which exhibited good modulation of γ-secretase activity, excellent pharmacokinetics and good central lowering of Aβ42 in Sprague-Dawley rats. 相似文献
2.
Lübbers T Flohr A Jolidon S David-Pierson P Jacobsen H Ozmen L Baumann K 《Bioorganic & medicinal chemistry letters》2011,21(21):6554-6558
We herein report the discovery of a new γ-secretase modulator class with an aminothiazole core starting from a HTS hit (3). Synthesis and SAR of this series are discussed. These novel compounds demonstrate moderate to good in vitro potency in inhibiting amyloid beta (Aβ) peptide production. Overall γ-secretase is not inhibited but the formation of the aggregating, toxic Aβ42 peptide is shifted to smaller non-aggregating Aβ peptides. Compound 15 reduced brain Aβ42 in vivo in APPSwe transgenic mice at 30mg/kg p.o. 相似文献
3.
Fischer C Shah S Hughes BL Nikov GN Crispino JL Middleton RE Szewczak AA Munoz B Shearman MS 《Bioorganic & medicinal chemistry letters》2011,21(2):773-776
Synthesis, SAR and evaluation of styrenyl quinazolinones as novel gamma secretase modulators are presented in this communication. Starting from literature and in-house leads we evaluated a range of quinazolinones which showed good modulation of γ-secretase activity. 相似文献
4.
Alexey Rivkin Sean P. Ahearn Stephanie M. Chichetti Christopher L. Hamblett Yudith Garcia Michelle Martinez Jed L. Hubbs Michael H. Reutershan Matthew H. Daniels Phieng Siliphaivanh Karin M. Otte Chaomin Li Andrew Rosenau Laura M. Surdi Joon Jung Bethany L. Hughes Jamie L. Crispino George N. Nikov Richard E. Middleton Christopher M. Moxham Mark S. Shearman 《Bioorganic & medicinal chemistry letters》2010,20(7):2279-2282
The development of a novel series of purines as γ-secretase modulators for potential use in the treatment of Alzheimer’s disease is disclosed herein. Optimization of a previously disclosed pyrimidine series afforded a series of potent purine-based γ-secretase modulators with 300- to 2000-fold in vitro selectivity over inhibition of Notch cleavage and that selectively reduces Αβ42 in an APP-YAC transgenic mouse model. 相似文献
5.
Wan Z Hall A Sang Y Xiang JN Yang E Smith B Harrison DC Yang G Yu H Price HS Wang J Hawkins J Lau LF Johnson MR Li T Zhao W Mitchell WL Su X Zhang X Zhou Y Jin Y Tong Z Cheng Z Hussain I Elliott JD Matsuoka Y 《Bioorganic & medicinal chemistry letters》2011,21(16):4832-4835
SAR of a novel series of pyridine-derived γ-secretase modulators is described. Compound 5 was found to be a potent modulator in vitro, which on further profiling, was found to decrease Aβ42 and Aβ40, and maintain (or increase) the levels of total Aβ. Furthermore, representative compounds 1 and 5 demonstrated in vivo efficacy to lower Aβ42 in the brain without altering Notch processing in the peripheral. 相似文献
6.
Wan Z Hall A Jin Y Xiang JN Yang E Eatherton A Smith B Yang G Yu H Wang J Ye L Lau LF Yang T Mitchell W Cai W Zhang X Sang Y Wang Y Tong Z Cheng Z Hussain I Elliott JD Matsuoka Y 《Bioorganic & medicinal chemistry letters》2011,21(13):4016-4019
SAR of a novel series of pyridazine-derived γ-secretase modulators is described. Compound 25 was found to be a potent modulator in vitro, which on further profiling, was found to decrease Aβ42 and Aβ40, and maintain the levels of total Aβ. Furthermore, 25 demonstrated excellent pharmacokinetic parameters as well as good CNS penetration in the rat. 相似文献
7.
Xin Z Peng H Zhang A Talreja T Kumaravel G Xu L Rohde E Jung MY Shackett MN Kocisko D Chollate S Dunah AW Snodgrass-Belt PA Arnold HM Taveras AG Rhodes KJ Scannevin RH 《Bioorganic & medicinal chemistry letters》2011,21(24):7277-7280
Starting from literature examples of nonsteroidal anti-inflammatory drugs (NSAIDs)-type carboxylic acid γ-secretase modulators (GSMs) and using a scaffold design approach, we identified 4-aminomethylphenylacetic acid 4 with a desirable γ-secretase modulation profile. Scaffold optimization led to the discovery of a novel chemical series, represented by 6b, having improved brain penetration. Further SAR studies provided analog 6q that exhibited a good pharmacological profile. Oral administration of 6q significantly reduced brain Aβ42 levels in mice and rats. 相似文献
8.
Close J Heidebrecht R Hendrix J Li C Munoz B Surdi L Kattar S Tempest P Moses P Geng X Hughes B Smotrov N Moxham C Chapnick J Kariv I Nikov G Burke JE Deshmukh S Jeliazkova-Mecheva V Leach JK Diaz D Xu L Yang Z Kwei G Moy L Shah S Tanga F Kenefic C Savage D Shearman M Ball RG McNevin MJ Markarewicz A Miller T 《Bioorganic & medicinal chemistry letters》2012,22(9):3203-3207
Alzheimer's disease is a major unmet medical need with pathology characterized by extracellular proteinaceous plaques comprised primarily of β-amyloid. γ-Secretase is a critical enzyme in the cellular pathway responsible for the formation of a range of β-amyloid peptides; one of which, Aβ42, is believed to be responsible for the neuropathological features of the disease. Herein, we report 4,4 disubstituted piperidine γ-secretase inhibitors that were optimized for in vitro cellular potency and pharmacokinetic properties in vivo. Key agents were further characterized for their ability to lower cerebral Aβ42 production in an APP-YAC mouse model. This structural series generally suffered from sub-optimal pharmacokinetics but hypothesis driven lead optimization enabled the discovery of γ-secretase inhibitors capable of lowering cerebral Aβ42 production in mice. 相似文献
9.
Qin J Dhondi P Huang X Mandal M Zhao Z Pissarnitski D Zhou W Aslanian R Zhu Z Greenlee W Clader J Zhang L Cohen-Williams M Jones N Hyde L Palani A 《Bioorganic & medicinal chemistry letters》2011,21(2):664-669
We herein report the discovery of four series of fused 5,6-bicyclic heterocycles as γ-secretase modulators. Synthesis and SAR of these series are discussed. These compounds represent a new class of γ-secretase modulators that demonstrate moderate to good in vitro potency in inhibiting Aβ42 production. 相似文献
10.
Fischer C Zultanski SL Zhou H Methot JL Shah S Nuthall H Hughes BL Smotrov N Hill A Szewczak AA Moxham CM Bays N Middleton RE Munoz B Shearman MS 《Bioorganic & medicinal chemistry letters》2012,22(9):3140-3146
Synthesis and SAR studies of novel aryl triazoles as gamma secretase modulators (GSMs) are presented in this communication. Starting from our aryl triazole leads, optimization studies were continued and the series progressed towards novel amides and lactams. Triazole 57 was identified as the most potent analog in this series, displaying single-digit nanomolar Aβ42 IC(50) in cell-based assays and reduced affinity for the hERG channel. 相似文献
11.
Daniel Oehlrich Frederik J.R. Rombouts Didier Berthelot François P. Bischoff Michel A.J. De Cleyn Libuse Jaroskova Gregor Macdonald Marc Mercken Michel Surkyn Andrés A. Trabanco Gary Tresadern Sven Van Brandt Adriana I. Velter Tongfei Wu Harrie J.M. Gijsen 《Bioorganic & medicinal chemistry letters》2013,23(17):4794-4800
The evolution of amide 3 into conformationally restricted bicyclic triazolo-piperidine 14-S as a γ-secretase modulator is described. This is a potential disease modifying anti-Alzheimer’s drug which demonstrated high in vitro and in vivo potency against Aβ42 peptide, reduced lipophilicity and enhanced brain free fraction compared to the previous series. 相似文献
12.
Eva Christine Naumann Stefan Göring Isabella Ogorek Sascha Weggen Boris Schmidt 《Bioorganic & medicinal chemistry letters》2013,23(13):3852-3856
Modulation of γ-secretase activity is a promising therapeutic strategy for the treatment of Alzheimer’s disease. Herein we report on the synthesis of carprofen- and tocopherol-derived small-molecule modulators carrying terpene moieties as lipophilic membrane anchors. Additionally, these modulators are equipped with an acidic moiety, which contributes to the desired modulatory effect on the γ-secretase with decreased formation of Aβ42 and increased Aβ38 production. 相似文献
13.
Ebke A Luebbers T Fukumori A Shirotani K Haass C Baumann K Steiner H 《The Journal of biological chemistry》2011,286(43):37181-37186
γ-Secretase is essential for the generation of the neurotoxic 42-amino acid amyloid β-peptide (Aβ(42)). The aggregation-prone hydrophobic peptide, which is deposited in Alzheimer disease (AD) patient brain, is generated from a C-terminal fragment of the β-amyloid precursor protein by an intramembrane cleavage of γ-secretase. Because Aβ(42) is widely believed to trigger AD pathogenesis, γ-secretase is a key AD drug target. Unlike inhibitors of the enzyme, γ-secretase modulators (GSMs) selectively lower Aβ(42) without interfering with the physiological function of γ-secretase. The molecular target(s) of GSMs and hence the mechanism of GSM action are not established. Here we demonstrate by using a biotinylated photocross-linkable derivative of highly potent novel second generation GSMs that γ-secretase is a direct target of GSMs. The GSM photoprobe specifically bound to the N-terminal fragment of presenilin, the catalytic subunit of γ-secretase, but not to other γ-secretase subunits. Binding was differentially competed by GSMs of diverse structural classes, indicating the existence of overlapping/multiple GSM binding sites or allosteric alteration of the photoprobe binding site. The β-amyloid precursor protein C-terminal fragment previously implicated as the GSM binding site was not targeted by the compound. The identification of presenilin as the molecular target of GSMs directly establishes allosteric modulation of enzyme activity as a mechanism of GSM action and may contribute to the development of therapeutically active GSMs for the treatment of AD. 相似文献
14.
Pettersson M Johnson DS Subramanyam C Bales KR am Ende CW Fish BA Green ME Kauffman GW Lira R Mullins PB Navaratnam T Sakya SM Stiff CM Tran TP Vetelino BC Xie L Zhang L Pustilnik LR Wood KM O'Donnell CJ 《Bioorganic & medicinal chemistry letters》2012,22(8):2906-2911
We report the discovery and optimization of a novel series of dihydrobenzofuran amides as γ-secretase modulators (GSMs). Strategies for aligning in vitro potency with drug-like physicochemical properties and good microsomal stability while avoiding P-gp mediated efflux are discussed. Lead compounds such as 35 and 43 have moderate to good in vitro potency and excellent selectivity against Notch. Good oral bioavailability was achieved as well as robust brain Aβ42 lowering activity at 100 mg/kg po dose. 相似文献
15.
François P. Bischoff Adriana Ingrid Velter Garrett Minne Serge Pieters Didier Berthelot Michel De Cleyn Harrie J.M. Gijsen Gregor Macdonald Michel Surkyn Sven Van Brandt Yves Van Roosbroeck Chiara Zavattaro Marc Mercken Nigel Austin Deborah Dhuyvetter Herman Borghys Ishtiyaque Ahmad Swapan Kumar Samanta 《Bioorganic & medicinal chemistry letters》2019,29(14):1737-1745
The discovery, design and synthesis of a new series of GSMs is described. The classical imidazole heterocycle has been replaced by a cyano group attached to an indole nucleus. The exploration of this series has led to compound 26-S which combined high in vitro and in vivo potency with an acceptable drug-like profile. 相似文献
16.
17.
Stefanie Baumann Nicole Höttecke Robert Schubenel Karlheinz Baumann Boris Schmidt 《Bioorganic & medicinal chemistry letters》2009,19(24):6986-6990
Selective lowering of Aβ42 levels with small-molecule substrate targeting γ-secretase modulators (sGSMs), such as some non-steroidal anti-inflammatory drugs, is a promising therapeutic approach for Alzheimer’s disease. Here we present N-substituted carbazole- and O-substituted fenofibrate-derived sGSMs and their activity data. Seven out of 19 screened compounds exhibited promising activity against Aβ42 secretion at a low micromolar level. We presume that the sGSMs interact with lys624 at the membrane interface and that the lipophilic substituents anchor the compound orientation in the membrane. 相似文献
18.
《Bioorganic & medicinal chemistry》2020,28(1):115132
Gamma-secretase modulators (GSMs) are promising disease-modifying drugs for Alzheimer’s disease because they can selectively decrease pathogenic amyloid-β42 (Aβ42) levels. Here we report the discovery of orally active N-ethylpyridine-2-carboxamide derivatives as GSMs. The isoindolinone moiety of 5-[8-(benzyloxy)-2-methylimidazo[1,2-a]pyridin-3-yl]-2-ethyl-2,3-dihydro-1H-isoindol-1-one hydrogen chloride (1a) was replaced with a picolinamide moiety. Optimization of the benzyl group significantly improved GSM activity and mouse microsomal stability. 5-{8-[([1,1′-Biphenyl]-4-yl)methoxy]-2-methylimidazo[1,2-a]pyridin-3-yl}-N-ethylpyridine-2-carboxamide hydrogen chloride (1v) potently reduced Aβ42 levels with an IC50 value of 0.091 µM in cultured cells without inhibiting CYP3A4. Moreover, 1v demonstrated a sustained pharmacokinetic profile and significantly reduced brain Aβ42 levels in mice. 相似文献
19.
《Bioorganic & medicinal chemistry letters》2014,24(1):378-381
The design, synthesis, and SAR of cyclic diamines as novel γ secretase modulators (GSMs) are presented in this Letter. Starting from information in the literature and in-house cyclic diamines library, we have found a 3(S)-aminopiperidine as a potent structure for lowering Aβ42 production both in vitro and in vivo. 相似文献
20.
Hieke M Ness J Steri R Greiner C Werz O Schubert-Zsilavecz M Weggen S Zettl H 《Bioorganic & medicinal chemistry》2011,19(18):5372-5382
A novel set of dual γ-secretase/PPARγ modulators characterized by a 2-benzyl hexanoic acid scaffold is presented. Synthetic efforts were focused on the variation of the substitution pattern of the central benzene. Finally, we obtained a new class of 2,5-disubstituted 2-benzylidene hexanoic acid derivatives, which act as dual γ-secretase/PPARγ modulators in the low micromolar range. We have explored broad SAR and successfully improved the dual pharmacological activity and the selectivity profile against potential off-targets such as NOTCH and COX. Compound 17 showed an IC(50) Aβ42=2.4 μM and an EC(50) PPARγ=7.2 μM and could be a valuable tool to further evaluate the concept of dual γ-secretase/PPARγ modulators in animal models of Alzheimer's disease. 相似文献