共查询到20条相似文献,搜索用时 0 毫秒
1.
Methot JL Chakravarty PK Chenard M Close J Cruz JC Dahlberg WK Fleming J Hamblett CL Hamill JE Harrington P Harsch A Heidebrecht R Hughes B Jung J Kenific CM Kral AM Meinke PT Middleton RE Ozerova N Sloman DL Stanton MG Szewczak AA Tyagarajan S Witter DJ Secrist JP Miller TA 《Bioorganic & medicinal chemistry letters》2008,18(3):973-978
We report herein the initial exploration of novel selective HDAC1/HDAC2 inhibitors (SHI-1:2). Optimized SHI-1:2 structures exhibit enhanced intrinsic activity against HDAC1 and HDAC2, and are greater than 100-fold selective versus other HDACs, including HDAC3. Based on the SAR of these agents and our current understanding of the HDAC active site, we postulate that the SHI-1:2 extend the existing HDAC inhibitor pharmacophore to include an internal binding domain. 相似文献
2.
Richard W. Heidebrecht Melissa Chenard Joshua Close William K. Dahlberg Judith Fleming Jonathan B. Grimm Julie E. Hamill Andreas Harsch Brian B. Haines Bethany Hughes Astrid M. Kral Richard E. Middleton Chandrasekhar Mushti Nicole Ozerova Alexander A. Szewczak Hongmei Wang Kevin Wilson David J. Witter J. Paul Secrist Thomas A. Miller 《Bioorganic & medicinal chemistry letters》2009,19(7):2053-2058
We report the preparation and structure–activity relationships of phosphorus-containing histone deacetylase inhibitors. A strong trend between decreasing phosphorus functional group size and superior mouse pharmacokinetic properties was identified. In addition, optimized candidates showed tumor growth inhibition in xenograft studies. 相似文献
3.
Solomon D. Kattar Laura M. Surdi Anna Zabierek Joey L. Methot Richard E. Middleton Bethany Hughes Alexander A. Szewczak William K. Dahlberg Astrid M. Kral Nicole Ozerova Judith C. Fleming Hongmei Wang Paul Secrist Andreas Harsch Julie E. Hamill Jonathan C. Cruz Candia M. Kenific Melissa Chenard Thomas A. Miller Scott C. Berk Paul Tempest 《Bioorganic & medicinal chemistry letters》2009,19(4):1168-1172
The successful application of both solid and solution phase library synthesis, combined with tight integration into the medicinal chemistry effort, resulted in the efficient optimization of a novel structural series of selective HDAC1/HDAC2 inhibitors by the MRL-Boston Parallel Medicinal Chemistry group. An initial lead from a small parallel library was found to be potent and selective in biochemical assays. Advanced compounds were the culmination of iterative library design and possess excellent biochemical and cellular potency, as well as acceptable PK and efficacy in animal models. 相似文献
4.
Wilson KJ Witter DJ Grimm JB Siliphaivanh P Otte KM Kral AM Fleming JC Harsch A Hamill JE Cruz JC Chenard M Szewczak AA Middleton RE Hughes BL Dahlberg WK Secrist JP Miller TA 《Bioorganic & medicinal chemistry letters》2008,18(6):1859-1863
An HTS screening campaign identified a series of low molecular weight phenols that showed excellent selectivity (>100-fold) for HDAC1/HDAC2 over other Class I and Class II HDACs. Evolution and optimization of this HTS hit series provided HDAC1-selective (SHI-1) compounds with excellent anti-proliferative activity and improved physical properties. Dose-dependent efficacy in a mouse HCT116 xenograft model was demonstrated with a phenylglycine SHI-1 analog. 相似文献
5.
Witter DJ Harrington P Wilson KJ Chenard M Fleming JC Haines B Kral AM Secrist JP Miller TA 《Bioorganic & medicinal chemistry letters》2008,18(2):726-731
A class of biaryl benzamides was identified and optimized as selective HDAC1&2 inhibitors (SHI-1:2). These agents exhibit selectivity over class II HDACs 4-7, as well as class I HDACs 3 and 8; providing examples of selective HDAC inhibitors for the HDAC isoforms most closely associated with cancer. The hypothesis for the increased selectivity is the binding of a pendant aromatic group in the internal cavity of the HDAC1&2 enzymes. SAR development based on an initial lead led to a series of potent and selective inhibitors with reduced off-target activity and tumor growth inhibition activity in a HCT-116 xenograft model. 相似文献
6.
Lindsley CW Zhao Z Leister WH Robinson RG Barnett SF Defeo-Jones D Jones RE Hartman GD Huff JR Huber HE Duggan ME 《Bioorganic & medicinal chemistry letters》2005,15(3):761-764
This letter describes the development of two series of potent and selective allosteric Akt kinase inhibitors that display an unprecedented level of selectivity for either Akt1, Akt2 or both Akt1/Akt2. An iterative analog library synthesis approach quickly provided a highly selective Akt1/Akt2 inhibitor that induces apoptosis in tumor cells and inhibits Akt phosphorylation in vivo. 相似文献
7.
Michael L. Curtin H. Robin Heyman Richard F. Clark Bryan K. Sorensen George A. Doherty T. Matthew Hansen Robin R. Frey Kathy A. Sarris Ana L. Aguirre Anurupa Shrestha Noah Tu Kevin Woller Marina A. Pliushchev Ramzi F. Sweis Min Cheng Julie L. Wilsbacher Peter J. Kovar Jun Guo Michael R. Michaelides 《Bioorganic & medicinal chemistry letters》2017,27(15):3317-3325
Herein we disclose SAR studies that led to a series of isoindoline ureas which we recently reported were first-in-class, non-substrate nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. Modification of the isoindoline and/or the terminal functionality of screening hit 5 provided inhibitors such as 52 and 58 with nanomolar antiproliferative activity and preclinical pharmacokinetics properties which enabled potent antitumor activity when dosed orally in mouse xenograft models. X-ray crystal structures of two inhibitors bound in the NAMPT active-site are discussed. 相似文献
8.
Bantscheff M Hopf C Savitski MM Dittmann A Grandi P Michon AM Schlegl J Abraham Y Becher I Bergamini G Boesche M Delling M Dümpelfeld B Eberhard D Huthmacher C Mathieson T Poeckel D Reader V Strunk K Sweetman G Kruse U Neubauer G Ramsden NG Drewes G 《Nature biotechnology》2011,29(3):255-265
The development of selective histone deacetylase (HDAC) inhibitors with anti-cancer and anti-inflammatory properties remains challenging in large part owing to the difficulty of probing the interaction of small molecules with megadalton protein complexes. A combination of affinity capture and quantitative mass spectrometry revealed the selectivity with which 16 HDAC inhibitors target multiple HDAC complexes scaffolded by ELM-SANT domain subunits, including a novel mitotic deacetylase complex (MiDAC). Inhibitors clustered according to their target profiles with stronger binding of aminobenzamides to the HDAC NCoR complex than to the HDAC Sin3 complex. We identified several non-HDAC targets for hydroxamate inhibitors. HDAC inhibitors with distinct profiles have correspondingly different effects on downstream targets. We also identified the anti-inflammatory drug bufexamac as a class IIb (HDAC6, HDAC10) HDAC inhibitor. Our approach enables the discovery of novel targets and inhibitors and suggests that the selectivity of HDAC inhibitors should be evaluated in the context of HDAC complexes and not purified catalytic subunits. 相似文献
9.
Caterina Torrisi Monica Bisbocci Raffaele Ingenito Jesus M. Ontoria Michael Rowley Carsten Schultz-Fademrecht Carlo Toniatti Philip Jones 《Bioorganic & medicinal chemistry letters》2010,20(2):448-452
A novel hexahydrobenzonaphthyridinone PARP-1 pharmacophore is reported, subsequent SAR exploration around this scaffold led to selective PARP-1 inhibitors with low nanomolar enzyme potency, displaying good cellular activity and promising rat PK properties. 相似文献
10.
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
11.
《Bioorganic & medicinal chemistry》2016,24(18):4008-4015
The structure–activity and structure–kinetic relationships of a series of novel and selective ortho-aminoanilide inhibitors of histone deacetylases (HDACs) 1 and 2 are described. Different kinetic and thermodynamic selectivity profiles were obtained by varying the moiety occupying an 11 Å channel leading to the Zn2+ catalytic pocket of HDACs 1 and 2, two paralogs with a high degree of structural similarity. The design of these novel inhibitors was informed by two ligand-bound crystal structures of truncated hHDAC2. BRD4884 and BRD7232 possess kinetic selectivity for HDAC1 versus HDAC2. We demonstrate that the binding kinetics of HDAC inhibitors can be tuned for individual isoforms in order to modulate target residence time while retaining functional activity and increased histone H4K12 and H3K9 acetylation in primary mouse neuronal cell culture assays. These chromatin modifiers, with tuned binding kinetic profiles, can be used to define the relation between target engagement requirements and the pharmacodynamic response of HDACs in different disease applications. 相似文献
12.
Gahman TC Herbert MR Lang H Thayer A Symons KT Nguyen PM Massari ME Dozier S Zhang Y Sablad M Rao TS Noble SA Shiau AK Hassig CA 《Bioorganic & medicinal chemistry letters》2011,21(22):6888-6894
We have identified and synthesized a series of imidazole containing dimerization inhibitors of inducible nitric oxide synthase (iNOS). The necessity of key imidazole and piperonyl functionality was demonstrated and SAR studies led to the identification of compound 35, which showed a dose dependant inhibition in multiple pain models, including tactile allodynia induced by spinal nerve ligation (Chung model). 相似文献
13.
Daniel R. Goldberg Stéphane De Lombaert Robert Aiello Patricia Bourassa Nicole Barucci Qing Zhang Vishwas Paralkar Adam J. Stein Melissa Holt Jim Valentine William Zavadoski 《Bioorganic & medicinal chemistry letters》2017,27(3):413-419
As a follow-up to the discovery of our spirocyclic proline-based TPH1 inhibitor lead, we describe the optimization of this scaffold. Through a combination of X-ray co-crystal structure guided design and an in vivo screen, new substitutions in the lipophilic region of the inhibitors were identified. This effort led to new TPH1 inhibitors with in vivo efficacy when dosed as their corresponding ethyl ester prodrugs. In particular, 15b (KAR5585), the prodrug of the potent TPH1 inhibitor 15a (KAR5417), showed robust reduction of intestinal serotonin (5-HT) levels in mice. Furthermore, oral administration of 15b generated high and sustained systemic exposure of the active parent 15a in rats and dogs. KAR5585 was selected for further pharmacological evaluation in disease models associated with a dysfunctional peripheral 5-HT system. 相似文献
14.
Das J Furch JA Liu C Moquin RV Lin J Spergel SH McIntyre KW Shuster DJ O'Day KD Penhallow B Hung CY Doweyko AM Kamath A Zhang H Marathe P Kanner SB Lin TA Dodd JH Barrish JC Wityak J 《Bioorganic & medicinal chemistry letters》2006,16(14):3706-3712
A series of structurally novel aminothiazole based small molecule inhibitors of Itk were prepared to elucidate their structure-activity relationships (SARs), selectivity, and cell activity in inhibiting IL-2 secretion in a Jurkat T-cell assay. Compound 3 is identified as a potent and selective Itk inhibitor which inhibits anti-TCR antibody induced IL-2 production in mice in vivo and was previously reported to reduce lung inflammation in a mouse model of ovalbumin induced allergy/asthma. 相似文献
15.
A series of hydroxamates (4a–4l) were prepared from p-aminobenzoic acid to inhibit HDAC8. The idea is to substitute rigid aromatic ring in place of less rigid piperazine ring of hydroxamates reported earlier by our group. It is expected to increase potency retaining the selectivity. Result obtained suggested that the modifications carried out retained the selectivity towards HDAC8 isoform and increasing the potency in very few cases. Increase in potency is also associated with variation in cap aryl region. Two compounds (4f & 4l) were found to inhibit HDAC8 at concentrations (IC50) less than 20 μM. 相似文献
16.
Matthew W. Martin Jennifer Y. Lee David R. Lancia Pui Yee Ng Bingsong Han Jennifer R. Thomason Maureen S. Lynes C. Gary Marshall Chiara Conti Alan Collis Monica Alvarez Morales Kshama Doshi Aleksandra Rudnitskaya Lili Yao Xiaozhang Zheng 《Bioorganic & medicinal chemistry letters》2018,28(12):2143-2147
N-Hydroxy-2-arylisoindoline-4-carboxamides are potent and selective inhibitors of HDAC11. The discovery, synthesis, and structure activity relationships of this novel series of inhibitors are reported. An advanced analog (FT895) displays promising cellular activity and pharmacokinetic properties that make it a useful tool to study the biology of HDAC11 and its potential use as a therapeutic target for oncology and inflammation indications. 相似文献
17.
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
18.
Timothy Forsyth Patrick C. Kearney Byung Gyu Kim Henry W.B. Johnson Naing Aay Arlyn Arcalas David S. Brown Vicky Chan Jeff Chen Hongwang Du Sergey Epshteyn Adam A. Galan Tai P. Huynh Mohamed A. Ibrahim Brian Kane Elena S. Koltun Grace Mann Lisa E. Meyr Matthew S. Lee Gary L. Lewis Peiwen Yu 《Bioorganic & medicinal chemistry letters》2012,22(24):7653-7658
We report the discovery of a series of 4-aryl-2-aminoalkylpyrimidine derivatives as potent and selective JAK2 inhibitors. High throughput screening of our in-house compound library led to the identification of hit 1, from which optimization resulted in the discovery of highly potent and selective JAK2 inhibitors. Advanced lead 10d demonstrated a significant dose-dependent pharmacodynamic and antitumor effect in a mouse xenograft model. Based upon the desirable profile of 10d (XL019) it was advanced into clinical trials. 相似文献
19.
Makoto Shiozaki Hiroto Imai Katsuya Maeda Tomoya Miura Katsutaka Yasue Akira Suma Masahiro Yokota Yosuke Ogoshi Julia Haas Andrew M. Fryer Ellen R. Laird Nicole M. Littmann Steven W. Andrews John A. Josey Takayuki Mimura Yuichi Shinozaki Hiromi Yoshiuchi Takashi Inaba 《Bioorganic & medicinal chemistry letters》2009,19(21):6213-6217
A series of 1-sulfonylaminocyclopropanecarboxylates was synthesized as ADAMTS-5 (Aggrecanase-2) inhibitors. After an intensive investigation of the central cyclopropane core including its absolute stereochemistry and substituents, we found compound 22 with an Agg-2 IC50 = 7.4 nM, the most potent ADAMTS-5 inhibitor reported so far. 相似文献
20.
Taotao Feng Hai Wang Hong Su Hui Lu Liqin Yu Xiaojin Zhang Haopeng Sun Qidong You 《Bioorganic & medicinal chemistry》2013,21(17):5339-5354
Histone deacetylases (HDACs) are significant enzymes involved in tumor genesis and development. Herein, we report a series of novel N-hydroxyfurylacryl-amide-based HDAC inhibitors, which are marked by introducing branched hydrophobic groups as the capping group. The inhibitory activity of the synthesized compounds against HDACs and several tumor cell lines are firstly determined. Fifteen compounds with promising activities are selected for further evaluation of target selectivity profile against recombinant human HDAC1, HDAC4 and HDAC6. Compounds 10a, 10b, 10d and 16a exhibit outstanding selectivity against HDAC6. Analysis of HDAC4 X-ray structure and HDAC1, HDAC6 homology model indicates that these enzyme differ significantly in the rim near the surface of the active site. Although TSA has been known as a pan-HDAC inhibitor, it exhibits outstanding selectivity for HDAC6 over HDAC4. For further physicochemical properties study, six compounds are chosen for determination of their physicochemical properties including log D7.4 and aqueous solubility. The results suggest that compounds with a smaller framework and with hydrophilicgroups are likely to have better aqueous solubility. 相似文献