- Br?nsted Acid Catalyzed Dearomatization by Intramolecular Hydroalkoxylation/Claisen Rearrangement: Diastereo- and Enantioselective Synthesis of Spirolactams
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Described herein is a novel Br?nsted acid catalyzed intramolecular hydroalkoxylation/Claisen rearrangement, allowing the practical and atom-economic synthesis of a range of valuable spirolactams from readily available ynamides in generally good to excellent yields with excellent diastereoselectivities and broad substrate scope. Importantly, an unexpected dearomatization of nonactivated arenes and heteroaromatic compounds is involved in this tandem sequence. Moreover, an asymmetric version of this tandem cyclization was also achieved by efficient kinetic resolution by chiral phosphoric acid catalysis. In addition, the [3,3]-rearrangement is shown to be kinetically preferred over the related [1,3]-rearrangement by theoretical calculations.
- Chen, Peng-Fei,Wang, Binju,Wu, Peng,Ye, Long-Wu,Zhou, Bo
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supporting information
p. 27164 - 27170
(2021/11/22)
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- ETHER COMPOUNDS AND USES THEREOF
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The present invention provides compounds that modulate protein function, to restore protein homeostasis and/or cell-cell adhesion. The invention provides methods of modulating protein-mediated diseases, such as cytokine-mediated diseases, disorders, conditions, or responses. Compositions of these compounds are also provided. Methods of treatment, amelioration, or prevention of protein-mediated diseases, disorders, and conditions are also provided.
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Paragraph 0247
(2019/03/12)
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- Identification of novel uracil derivatives incorporating benzoic acid moieties as highly potent Dipeptidyl Peptidase-IV inhibitors
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Dipeptidyl Peptidase-IV (DPP-4) is a validated therapeutic target for type 2 diabetes. Aiming to interact with both residues Try629 and Lys554 in S2′ site, a series of novel uracil derivatives 1a–l and 2a–i incorporating benzoic acid moieties at the N3 position were designed and evaluated for their DPP-4 inhibitory activity. Structure-activity relationships (SAR) study led to the identification of the optimal compound 2b as a potent and selective DPP-4 inhibitor (IC50 = 1.7 nM). Docking study revealed the additional salt bridge formed between the carboxylic acid and primary amine of Lys554 has a key role in the enhancement of the activity. Furthermore, compound 2b exhibited no cytotoxicity in human hepatocyte LO2 cells up to 50 μM. Subsequent in vivo evaluations revealed that the ester of 2b robustly improves the glucose tolerance in normal mice. The overall results have shown that compound 2b has the potential to a safe and efficacious treatment for T2DM.
- Huang, Junli,Deng, Xiaoyan,Zhou, Siru,Wang, Na,Qin, Yujun,Meng, Liuwei,Li, Guobao,Xiong, Yuhua,Fan, Yating,Guo, Ling,Lan, Danni,Xing, Junhao,Jiang, Weizhe,Li, Qing
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p. 644 - 654
(2019/01/14)
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- Rapid generation of novel benzoic acid–based xanthine derivatives as highly potent, selective and long acting DPP-4 inhibitors: Scaffold-hopping and prodrug study
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A series of novel xanthine derivatives 2a-l incorporating benzoic acid moieties were rapidly generated by using strategy of scaffold-hopping from our previously reported scaffold uracil to xanthine, a scaffold of approved drug linagliptin. After systematic structure-activity relationship (SAR) study around benzoic acid moieties, 5 novel DPP-4 inhibitors with low picomolar potency range (IC50 50 value of 0.1 nM for DPP-4, showed 22-fold improvement in inhibitory activity compared to lead compound uracil 1, its activity was 45-fold more potent than alogliptin. 2e, 2f, 2i and 2k were selected for pharmacokinetic evaluation, and 2f and 2i showed the better pharmacokinetic profiles after iv administration, but poor oral bioavailability. To improve the oral pharmacokinetic profile, prodrug design approach was performed around 2f and 2i. Esters of 2f and 2i were synthesized and evaluated for stability, toxicity and pharmacokinetics. Compound 3e, the methyl ester of compound 2f, was identified to demonstrate good stability, low toxicity and improved oral bioavailability, with 3-fold higher blood concentration compared to 2f in rats. The following in vivo evaluations revealed 3e provided a sustained pharmacodynamics effect for 48h, and robustly improved glucose tolerance in normal ICR and db/db mice in dose-dependent manner. Chronic treatments investigations demonstrated that 3e achieved more beneficial effects on fasting blood glucose levels and glucose tolerance than alogliptin in type 2 diabetic db/db mice. The overall results have shown that compound 3e has the potential to efficacious, safety and long-acting treatment for T2DM.
- Li, Qing,Meng, Liuwei,Zhou, Siru,Deng, Xiaoyan,Wang, Na,Ji, Yi,Peng, Yichun,Xing, Junhao,Yao, Gongmei
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p. 509 - 523
(2019/07/25)
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- Assessment of the regioselectivity in the condensation reaction of unsymmetrical o-phthaldialdehydes with alanine
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One approach for the synthesis of isoindolinones, a privileged bioactive heterocyclic core structure, involves a condensation reaction of o-phthaldialdehydes with a suitable nitrogen-containing nucleophile. This fascinating reaction is revisited here in the context of the use of o-phthaldialdehydes that contain additional substituents in the aromatic ring leading to a detailed analysis of the regioselectivity of the reaction. Eleven monosubstituted o-phthaldialdehydes were synthesised and reacted with alanine. The regioselectivity observed across the eleven substrates led to the design of a disubstituted substrate that reacted with very high control. A gram-scale reaction followed by esterification gave one major regioisomer in high yield. In addition, the regioselectivity observed on reaction of two novel monodeuterated substrates led to an increased mechanistic understanding.
- D'Hollander, Agathe C.A.,Westwood, Nicholas J.
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p. 224 - 239
(2017/12/08)
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- Development of Novel Inhibitors for Histone Methyltransferase SET7/9 based on Cyproheptadine
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The histone methyltransferase SET7/9 methylates not only histone but also non-histone proteins as substrates, and therefore, SET7/9 inhibitors are considered candidates for the treatment of diseases. Previously, our group identified cyproheptadine, used clinically as a serotonin receptor antagonist and histamine receptor (H1) antagonist, as a novel scaffold of the SET7/9 inhibitor. In this work, we focused on dibenzosuberene as a substructure of cyproheptadine and synthesized derivatives with various functional groups. Among them, the compound bearing a 2-hydroxy group showed the most potent activity. On the other hand, a 3-hydroxy group or another hydrophilic functional group such as acetamide decreased the activity. Structural analysis clarified a rationale for the improved potency only by tightly restricted location and type of the hydrophilic group. In addition, a SET7/9 loop, which was only partially visible in the complex with cyproheptadine, became more clearly visible in the complex with 2-hydroxycyproheptadine. These results are expected to be helpful for further structure-based development of SET7/9 inhibitors.
- Hirano, Tomoya,Fujiwara, Takashi,Niwa, Hideaki,Hirano, Michitake,Ohira, Kasumi,Okazaki, Yusuke,Sato, Shin,Umehara, Takashi,Maemoto, Yuki,Ito, Akihiro,Yoshida, Minoru,Kagechika, Hiroyuki
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p. 1530 - 1540
(2018/08/01)
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- Iron(II) promoted direct synthesis of dibenzo[b,e]oxepin-11(6H)-one derivatives with biological activity. A short synthesis of doxepin
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A novel and efficient synthesis of dibenzo[b,e]oxepin-11(6H)-ones by direct intramolecular ortho-acylation from readily available 2-(phenoxymethyl)benzoic acids was developed. The method takes advantage of a newly developed cooperative system consisting of sustainable FeCl2 and Cl2CHOCH3 as the key components. This methodology is compatible with a wide variety of functional groups in good to excellent yields and high regioselectivity. The synthetic application of new protocol was extended to the synthesis of known tricyclic drug doxepin as well as a small library of oxepin based derivatives. For the first time, the obtained dibenzo[b,e]oxepinone derivatives were evaluated for their biological activities on the free-living nematode Caenorhabditis elegans as an effective and cost-efficient model system for anthelmintic discovery.
- Scoccia, Jimena,Castro, M. Julia,Faraoni, M. Belén,Bouzat, Cecilia,Martín, Víctor S.,Gerbino, Darío C.
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supporting information
p. 2913 - 2922
(2017/04/26)
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- Series of structural and functional models for the ES (enzyme-substrate) complex of the Co(II)-containing quercetin 2,3-dioxygenase
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A series of mononuclear CoII-flavonolate complexes [Co IILR(fla)] (LRH = 2-{[bis(pyridin-2-ylmethyl) amino]methyl}-p/m-R-benzoic acid; R = p-OMe (1), p-Me (2), m-Br (4), and m-NO2 (5); fla = flavonolate) were designed and synthesized as structural and functional models for the ES (enzyme-substrate) complexes to mimic the active site of the Co(II)-containing quercetin 2,3-dioxygenase (Co-2,3-QD). The metal center Co(II) ion in each complex shows a similar distorted octahedral geometry. The model complexes display high enzyme-type dioxygenation reactivity (oxidative O-heterocyclic ring opening of the coordinated substrate flavonolate) at low temperature, presumably due to the attached carboxylate group in the ligands. The reactivity exhibits a substituent group dependent order of -OMe (1) > -Me (2) > -H (3)14b > -Br (4) > -NO2 (5), and the Hammett plot is linear (ρ = -0.78). This can be explained as the electronic nature of the substituent group in the ligands may influence the conformation and redox potential of the bound flavonolate and finally bring different reactivity. The structures, properties, and reactivity of the model complexes show some dependence on the substituent group in the supporting model ligands, and there is some relationship among them. This study is the first example of a series of structural and functional ES models of Co-2,3-QD, with focus on the effects of the electronic nature of substituted groups and the carboxylate group of the ligands to the dioxygenation reactivity, that will provide important insights into the structure-property-reactivity relationship and the catalytic role of Co-2,3-QD.
- Sun, Ying-Ji,Huang, Qian-Qian,Zhang, Jian-Jun
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p. 2932 - 2942
(2014/04/03)
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- Isosteric analogs of lenalidomide and pomalidomide: Synthesis and biological activity
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A series of analogs of the immunomodulary drugs lenalidomide (1) and pomalidomide (2), in which the amino group is replaced with various isosteres, was prepared and assayed for immunomodulatory activity and activity against cancer cell lines. The 4-methyl and 4-chloro analogs 4 and 15, respectively, displayed potent inhibition of tumor necrosis factor-α (TNF-α) in LPS-stimulated hPBMC, potent stimulation of IL-2 in a human T cell co-stimulation assay, and anti-proliferative activity against the Namalwa lymphoma cell line. Both of these analogs displayed oral bioavailability in rat.
- Ruchelman, Alexander L.,Man, Hon-Wah,Zhang, Weihong,Chen, Roger,Capone, Lori,Kang, Jian,Parton, Anastasia,Corral, Laura,Schafer, Peter H.,Babusis, Darius,Moghaddam, Mehran F.,Tang, Yang,Shirley, Michael A.,Muller, George W.
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p. 360 - 365
(2013/02/23)
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- Metabolically stable dibenzo[ b, e ]oxepin-11(6 H)-ones as highly selective p38 MAP kinase inhibitors: Optimizing anti-cytokine activity in human whole blood
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Five series of metabolically stable disubstituted dibenzo[b,e]oxepin-11(6H) -ones were synthesized and tested in a p38α enzyme assay for their inhibition of tumor necrosis factor-α (TNF-α) release in human whole blood. Compared to the monosubstituted dibenzo[b,e]oxepin-11(6H)-one derivatives, it has been shown that the additional introduction of hydrophilic residues at position 9 leads to a substantial improvement of the inhibitory potency and metabolic stability. Using protein X-ray crystallography, the binding mode of the disubstituted dibenzoxepinones and the induction of a glyince flip in the hinge region were confirmed. The most potent compound of this series, 32e, shows an outstanding biological activity on isolated p38α, with an IC50 value of 1.6 nM, extraordinary selectivity (by a factor >1000, Kinase WholePanelProfiler), and low ATP competitiveness. The ability to inhibit the release of TNF-α from human whole blood was optimized down to an IC50 value of 125 nM. With the promising dibenzoxepinone inhibitor 3i, a pharmacokinetic study in mice was conducted.
- Baur, Benjamin,Storch, Kirsten,Martz, Kathrin E.,Goettert, Marcia I.,Richters, André,Rauh, Daniel,Laufer, Stefan A.
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p. 8561 - 8578
(2013/12/04)
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- Design and synthesis of pyrrolo[3,2- d ]pyrimidine human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) dual inhibitors: Exploration of novel back-pocket binders
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To develop novel human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) kinase inhibitors, we explored pyrrolo[3,2-d]pyrimidine derivatives bearing bicyclic fused rings designed to fit the back pocket of the HER2/EGFR proteins. Among them, the 1,2-benzisothiazole (42m) ring was selected as a suitable back pocket binder because of its potent HER2/EGFR binding and cell growth inhibitory (GI) activities and pseudoirreversibility (PI) profile as well as good bioavailability (BA). Ultimately, we arrived at our preclinical candidate 51m by optimization of the N-5 side chain to improve CYP inhibition and metabolic stability profiles without a loss of potency (HER2/EGFR inhibitory activity, IC50, 0.98/2.5 nM; and GI activity BT-474 cells, GI50, 2.0 nM). Reflecting the strong in vitro activities, 51m exhibited potent tumor regressive efficacy against both HER2- and EGFR-overexpressing tumor (4-1ST and CAL27) xenograft models in mice at oral doses of 50 mg/kg and 100 mg/kg.
- Kawakita, Youichi,Banno, Hiroshi,Ohashi, Tomohiro,Tamura, Toshiya,Yusa, Tadashi,Nakayama, Akiko,Miki, Hiroshi,Iwata, Hidehisa,Kamiguchi, Hidenori,Tanaka, Toshimasa,Habuka, Noriyuki,Sogabe, Satoshi,Ohta, Yoshikazu,Ishikawa, Tomoyasu
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experimental part
p. 3975 - 3991
(2012/07/16)
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- HEDGEHOG INHIBITORS
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Described herein are compounds, pharmaceutical compositions and methods for the inhibition of hedgehog signaling. Said compounds, pharmaceutical compositions and methods have utility in the treatment of human and veterinary disease and disorders.
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Page/Page column 36
(2011/08/03)
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- HEDGEHOG INHIBITORS
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Described herein are compounds, pharmaceutical compositions and methods for the inhibition of Hedgehog signaling. Said compounds, pharmaceutical compositions and methods have utility in the treatment of human and veterinary disease and disorders.
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Page/Page column 56
(2011/08/03)
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- FARNESOID X RECEPTOR AGONISTS
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The present invention relates to famesoid X receptors (FXR, NR1H4) FXR is a member of the nuclear receptor class of ligand-activate transcription factors More particularly, the present invention relates to compounds useful as agonists for FXR, pharmaceutical formulations comprising such compounds, and therapeutic use of the same Novel isoxazole compounds are disclosed as part of pharmaceutical compositions for the treatment of a condition mediated by decreased FXR activity, such as obesity, diabetes, cholestatic liver disease, liver fibrosis, and metabolic syndrome
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Page/Page column 214
(2009/03/07)
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- BENZOIMIDAZOLE, TETRAHYDRO-QUINOXALINE, BENZOTRIAZOLE, DIHYDRO-IMIDAZO[4,5-c] PYRIDINONE AND DIHYDRO-ISOINDOLONE DERIVATIVES
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This invention relates to compounds of the formula wherein A, R1 to R3 are as defined in the specification and G is benzoimidazole, quinoxaline, benzotriazole, dihydro-imidazo[4,5-c]pyridine and dihydro-isoindolone group as defined in the specification, and pharmaceutically acceptable salts thereof. The invention further relates to pharmaceutical compositions containing such compounds, to a process for their preparation and to their use for the treatment and/or prevention of diseases which are associated with the modulation of SST receptors subtype 5.
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Page/Page column 40
(2008/12/08)
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- ISOINDOLE DERIVATIVES
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This invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, a process of making these compounds, pharmaceutical compositions containing one or more of these compounds or their salts, and their use for the treatment of schizophrenia, bipolar disorder, or other central nervous system disorders.
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Page/Page column 35
(2010/11/30)
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- Isoindol-1,3-dione and isoindol-1-one derivatives with high binding affinity to β-amyloid fibrils
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Based on the structural features of Indoprofen and PIB, a series of isoindol-1,3-diones 1a-k and isoindol-1-ones 2a-l were designed and synthesized. These 23 compounds were evaluated by competitive binding assay against aggregated Aβ42 fibrils using [125I]TZDM. All the isoindolone derivatives showed very good binding affinities with Ki values in the subnanomolar range (0.42-0.94 nM). Among them, isoindol-1,3-diones 1i and 1k and isoindol-1-ones 2c and 2i exhibited excellent binding affinities (Ki = 0.42-0.44 and 0.46-0.49 nM) than those of Indoprofen (Ki = 0.52 nM) and PIB (Ki = 0.70 nM). These results suggest that isoindolones could be served as a scaffold for potential AD diagnostic probes to monitor Aβ fibrils.
- Lee, Hyu Ji,Lim, Soo Jeong,Oh, Seung Jun,Moon, Dae Hyuk,Kim, Dong Jin,Tae, Jinsung,Yoo, Kyung Ho
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p. 1628 - 1631
(2008/09/19)
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- BICYCLIC DERIVATIVES AS P38 KINASE INHIBITORS
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New bicyclic derivatives of formula (I); wherein the meanings for the various substituents are as disclosed in the description. These compounds are useful as p38 kinase inhibitors.
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Page/Page column 39
(2010/11/25)
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- HYDANTOIN DERIVATIVES FOR THE TREATMENT OF INFLAMMATORY DISORDERS
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This invention relates to compounds of Formula (1) or a pharmaceutically acceptable salt, solvate or isomer thereof, which can be useful for the treatment of diseases or conditions mediated by MMPs, ADAMs, TACE, TNF- or combinations thereof.
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Page column 90
(2008/06/13)
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- ISOINDOLONE COMPOUNDS AND THEIR USE AS METABOTROPIC GLUTAMATE RECEPTOR POTENTIATORS
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The present invention is directed to compounds of formula (I), wherein R1 is a ring and n is a number from 1 to 8. The invention also relates to use of the compounds in therapy as metabotropic glutamate receptor modulators, particularly in neurological and psychiatric disorders.
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Page/Page column 62-63
(2008/06/13)
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- 2,3-DIHYDRO-ISOINDOL-1-ONES WITH MAO-B INHIBITING ACTIVITY
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2,3 Dihydro-isoindol-1-one derivatives, processes for their production, their use as pharmaceuticals and pharmaceutical compositions comprising them, for the prevention and treatment of diseases which are mediated by monoamine oxidase B inhibitors.
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- New Syntheses of Phenanthrenes and of Related Systems by Intramolecular Annulation Processes
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A regio- and stereoselective intramolecular double annulation, which converts monocyclic aromatic compounds into partly reduced phenanthrenes, is described.Methoxy- (9a,c) and benzene derivatives (9b) with a (5-bromoalkyl)mal
- Ghera, Eugene,Maurya, Rakesh,Ben-David, Yoshua
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p. 1912 - 1918
(2007/10/02)
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