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Van Goethem S Van der Veken P Dubois V Soroka A Lambeir AM Chen X Haemers A Scharpé S De Meester I Augustyns K 《Bioorganic & medicinal chemistry letters》2008,18(14):4159-4162
To obtain selective and potent inhibitors of dipeptidyl peptidases 8 and 9, we synthesized a series of substituted isoindolines as modified analogs of allo-Ile-isoindoline, the reference DPP8/9 inhibitor. The influence of phenyl substituents and different P2 residues on the inhibitors’ affinity toward other DPPs and more specifically, their potential to discriminate between DPP8 and DPP9 will be discussed. Within this series compound 8j was shown to be a potent and selective inhibitor of DPP8/9 with low activity toward DPP II. 相似文献
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Pap JS Kripli B Váradi T Giorgi M Kaizer J Speier G 《Journal of inorganic biochemistry》2011,105(6):911-918
Recently, a series of Fe(II) complexes have been published by our group with 3 N-donor 1,3-bis(2′-Ar-imino)isoindoline ligands containing various Ar-groups (pyridyl, 4-methylpyridyl, thiazolyl, benzimidazolyl and N-methylbenzimidazolyl). The superoxide scavenging activity of the compounds showed correlation with the Fe(III)/Fe(II) redox potentials. Analogous, electroneutral chelate complexes with Mn(II) and Ni(II) in 2:1 ligand:metal composition are reported here. Each Mn(II) complex exhibits one reversible redox wave that is assigned as the Mn(III)/Mn(II) redox transition. The E1/2 spans a 180 mV range from − 98 (Ar = 3-methylpyridyl) to 82 mV (Ar = thiazolyl) vs. the Fc+/Fc depending on the Ar-sidearm. The SOD-like (SOD=superoxide dismutase)activity of all complexes was determined according to the McCord-Fridovich method. The Mn(II) isoindolinates have IC50 values - determined with 50 μM cytochrome c Fe(III) - that range from (3.22 ± 0.39) × 10− 6 (Ar = benzimidazolyl) to (10.80 ± 0.54) × 10− 6 M (Ar = N-methylbenzimidazolyl). In contrast with the Fe(II) complexes, the IC50 concentrations show no significant dependence on the E1/2 values in this narrow potential range emphasizing that the redox potential is not the governing factor in the Mn(II)-containing scavengers. The analogous Ni(II) compounds show no redox transitions in the thermodynamically relevant potential range (− 0.40 to 0.65 V vs. SCE) and accordingly, their superoxide scavenging activity (if any) is below the detection level. 相似文献
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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
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A group of novel isoindoline hybrids incorporating oxime, hydrazone, pyrazole, chalcone or aminosulfonyl pharmacophores (9–14) was designed and characterized by spectral data and elemental analyses results. All newly synthesized compounds were evaluated as COX-2 inhibitors, anti-inflammatory and analgesic agents. Six hybrid derivatives (10b, 10c, 11a, 11d, 13, 14) were moderate COX-2 inhibitors (IC50 = 0.11–0.18 µM) close to standard celecoxib (IC50 = 0.09 µM). The most active compounds showed outstanding in vivo anti-inflammatory activity (% edema inhibition = 41.7–50, 1 h; 40.7–67.4, 3 h; 20–46.7, 6 h) better than reference drug diclofenac (% edema inhibition = 29.2, 1 h; 22.2, 3 h; 20, 6 h). Most compounds showed significant peripheral and/or central analgesic activity. The moderate selective COX-2 inhibitor; dimethoxychalcone 11d (SI = 103) displayed excellent anti-inflammatory activity (% edema inhibition = 45.8–59.3) and increased thermal pain threshold (50–92.85%) comparable to piroxicam (75%). Molecular docking studies have been established. 相似文献
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Müller A Höfner G Renukappa-Gutke T Parsons CG Wanner KT 《Bioorganic & medicinal chemistry letters》2011,21(19):5795-5799
We report a series of new stereoisomeric γ-amino alcohols comprising an N-methyl isoindoline moiety as ligands for the ifenprodil binding site of the NMDA receptor. Among the four series of stereoisomers, 8a-c, 9a-c, 10a-c, and 11a-c, synthesised, the highest potencies and NMDA-NR2B subtype selectivity was found for the methyl derivative 11a and the chloro derivative 11c, both possessing the [1S,1'S] configuration. However, additional moderate potency of 11a and 11c at the hERG channel with values of 2.6 ± 2.4% and 1.6 ± 2.0%, respectively, rendered them unsuitable for medical use. 相似文献
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Shultz M Fan J Chen C Cho YS Davis N Bickford S Buteau K Cao X Holmqvist M Hsu M Jiang L Liu G Lu Q Patel C Suresh JR Selvaraj M Urban L Wang P Yan-Neale Y Whitehead L Zhang H Zhou L Atadja P 《Bioorganic & medicinal chemistry letters》2011,21(16):4909-4912
The design, synthesis and biological evaluation of a novel series of isoindoline-based hydroxamates is described. Several analogs were shown to inhibit HDAC1 with IC50 values in the low nanomolar range and inhibit cellular proliferation of HCT116 human colon cancer cells in the sub-micromolar range. The cellular potency of compound 17e was found to have greater in vitro anti-proliferative activity than several compounds in late stage clinical trials for the treatment of cancer. The in vitro safety profiles of selected compounds were assessed and shown to be suitable for further lead optimization. 相似文献
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József S. Pap Vanda Bányai László Korecz Dávid Árus Gábor Speier 《Inorganica chimica acta》2011,376(1):158-169
Reaction of 1,3-bis(2′-Ar-imino)isoindolines (HLn, n = 1-7, Ar = benzimidazolyl, N-methylbenzimidazolyl, thiazolyl, pyridyl, 3-methylpyridyl, 4-methylpyridyl, and benzthiazolyl, respectively) with Cu(OCH3)2 yields mononuclear hexacoordinate complexes with Cu(Ln)2 composition. With cupric perchlorate square-pyramidal [CuII(HLn)(NCCH3)(OClO3)]ClO4 complexes (n = 1, 3, 4) were isolated as perchlorate salts, whereas with chloride CuII(HLn)Cl2 (n = 1, 4), or square-planar CuIICl2(HLn) (n = 2, 3, 7) complexes are formed. The X-ray crystal structures of Cu(L3)2, Cu(L5)2, [CuII(HL4)(NCCH3)(OClO3)]ClO4, CuIICl(L2) and CuIICl(L7) are presented along with electrochemical and spectral (UV-Vis, FT-IR and X-band EPR) characterization for each compound. When combined with base, the isoindoline ligands in the [CuII(HLn)(NCCH3)(OClO3)]ClO4 complexes undergo deprotonation in solution that is reversible and induces UV-Vis spectral changes. Equilibrium constants for the dissociation are calculated. X-band EPR measurements in frozen solution show that the geometry of the complexes is similar to the corresponding X-ray crystallographic structures. The superoxide scavenging activity of the compounds determined from the McCord-Fridovich experiment show dependence on structural features and reduction potentials. 相似文献
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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
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