cas 161975-39-9, 1-BOC-4-METHANESULFONYLOXYMETHYL-PIPERIDINE

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Selective, Small-Molecule Co-Factor Binding Site Inhibition of a Su(var)3-9, Enhancer of Zeste, Trithorax Domain Containing Lysine Methyltransferase
The first chemical probe to primarily occupy the co-factor binding site of a Su(var)3-9, enhancer of a zeste, trithorax (SET) domain containing protein lysine methyltransferase (PKMT) is reported. Protein methyltransferases require S-adenosylmethionine (SAM) as a co-factor (methyl donor) for enzymatic activity. However, SAM itself represents a poor medicinal chemistry starting point for a selective, cell-active inhibitor given its extreme physicochemical properties and its role in multiple cellular processes. A previously untested medicinal chemistry strategy of deliberate file enrichment around molecules bearing the hallmarks of SAM, but with improved lead-like properties from the outset, yielded viable hits against SET and MYND domain-containing protein 2 (SMYD2) that were shown to bind in the co-factor site. These leads were optimized to identify a highly biochemically potent, PKMT-selective, and cell-active chemical probe. While substrate-based inhibitors of PKMTs are known, this represents a novel, co-factor-derived strategy for the inhibition of SMYD2 which may also prove applicable to lysine methyltransferase family members previously thought of as intractable.
Taylor, Alexandria P.,Swewczyk, Magdalena,Kennedy, Steven,Trush, Viacheslav V.,Wu, Hong,Zeng, Hong,Dong, Aiping,Ferreira De Freitas, Renato,Tatlock, John,Kumpf, Robert A.,Wythes, Martin,Casimiro-Garcia, Agustin,Denny, Rajiah Aldrin,Parikh, Mihir D.,Li, Fengling,Barsyte-Lovejoy, Dalia,Schapira, Matthieu,Vedadi, Masoud,Brown, Peter J.,Arrowsmith, Cheryl H.,Owen, Dafydd R.
p. 7669 - 7683
(2019)
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INDOLE DERIVATIVES AND USES THEREOF FOR TREATING A CANCER
The present invention relates to indole derivatives of formula (I') as CK2 inhibitor and pharmaceutical compositions comprising the same. The present invention further relates to the use of such compounds of formula (I) for use for preventing and/or treating a cancer.
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(2022/02/06)

Design, synthesis and biological evaluation of Tozadenant analogues as adenosine A2A receptor ligands
With the aim to obtain potent adenosine A2A receptor (A2AR) ligands, a series of eighteen derivatives of 4-hydroxy-N-(4-methoxy-7-morpholin-4-yl-1,3-benzo[d]thiazol-2-yl)-4-methylpiperidine-1-carboxamide (SYN-115, Tozadenant) were designed and synthesized. The target compounds were obtained by a chemical building block principle that involved reaction of the appropriate aminobenzothiazole phenyl carbamates with either commercially available or readily synthesized functionalized piperidines. Their affinity and subtype selectivity with regard to human adenosine A1-and A2A receptors were determined using radioligand binding assays. Ki values for human A2AR ranged from 2.4 to 38 nM, with more than 120-fold selectivity over A1 receptors for all evaluated compounds except 13k which had a Ki of 361 nM and 18-fold selectivity. The most potent fluorine-containing derivatives 13e, 13g and 13l exhibited Ki values of 4.9 nM, 3.6 nM and 2.8 nM for the human A2AR. Interestingly, the corresponding values for rat A2AR were found to be four to five times higher. Their binding to A2AR was further confirmed by radiolabeling with 18F and in vitro autoradiography in rat brain slices, which showed almost exclusive striatal binding and complete displacement by the A2AR antagonist ZM 241385. We conclude that these compounds represent potential candidates for the visualization of the A2A receptor and open pathways to novel therapeutic treatments of neurodegenerative disorders or cancer.
Renk, Dana R.,Skraban, Marcel,Bier, Dirk,Schulze, Annette,Wabbals, Erika,Wedekind, Franziska,Neumaier, Felix,Neumaier, Bernd,Holschbach, Marcus
(2021/02/09)

Synthesis and evaluation of tetrahydroisoquinoline derivatives against Trypanosoma brucei rhodesiense
Human African Trypanosomiasis (HAT) is a neglected tropical disease caused by the parasitic protozoan Trypanosoma brucei (T. b.), and affects communities in sub-Saharan Africa. Previously, analogues of a tetrahydroisoquinoline scaffold were reported as having in vitro activity (IC50 = 0.25–70.5 μM) against T. b. rhodesiense. In this study the synthesis and antitrypanosomal activity of 80 compounds based around a core tetrahydroisoquinoline scaffold are reported. A detailed structure activity relationship was revealed, and five derivatives (two of which have been previously reported) with inhibition of T. b. rhodesiense growth in the sub-micromolar range were identified. Four of these (3c, 12b, 17b and 26a) were also found to have good selectivity over mammalian cells (SI > 50). Calculated logD values and preliminary ADME studies predict that these compounds are likely to have good absorption and metabolic stability, with the ability to passively permeate the blood brain barrier. This makes them excellent leads for a blood-brain barrier permeable antitrypanosomal scaffold.
Cullen, Danica R.,Gallagher, Ashlee,Duncan, Caitlin L.,Pengon, Jutharat,Rattanajak, Roonglawan,Chaplin, Jason,Gunosewoyo, Hendra,Kamchonwongpaisan, Sumalee,Payne, Alan,Mocerino, Mauro
(2021/10/07)

HETEROCYCLIC COMPOUNDS AS KINASE INHIBITORS
Heterocyclic compounds as CDK4 or CDK6 or other CDK inhibitors are provided. The compounds may find use as therapeutic agents for the treatment of diseases and may find particular use in oncology.
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Paragraph 0173

(2021/02/19)

ION CHANNEL ANTAGONISTS/BLOCKERS AND USES THEREOF
Provided are ion channel antagonists/blockers and uses thereof. Specifically, it provides the compounds of formula (I) or pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs, preparation method therefor and application thereof. Definition of each group in the formula can be found in the specification for details. Provided is also pharmaceutical composition useful for treatment of heart disease and other ion channel related diseases.
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Page/Page column 22; 24; 93-95

(2021/06/22)

BRD9 BIFUNCTIONAL DEGRADERS AND THEIR METHODS OF USE
The disclosure provides BRD9 bifunctional compounds of Formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, to their preparation, to pharmaceutical compositions comprising them, and to their use in the treatment of diseases and disorders mediated by a bromodomain-containing protein, such as bromodoma in-containing protein 9 (BRD9)
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Page/Page column 188

(2021/04/01)

SIGMA-1 RECEPTOR LIGANDS AND USES THEREOF
The present invention relates to the field of medicine. More specifically, the present invention relates to compounds that are sigma-1 receptor agonists and their use for the treatment of central nervous system disorders, including cognitive or neurodegen
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Page/Page column 35-36

(2021/06/26)

PYRIMIDINYL GROUP-CONTAINING TRICYCLIC COMPOUND SERVING AS C-MET INHIBITOR
Disclosed are a pyrimidinyl group-containing tricyclic compound and applications thereof in preparing a cancer-treating medicament. Specifically disclosed are a compound as represented by formula (I), a pharmaceutically acceptable salt of same, or an isomer thereof.
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Paragraph 0106; 0119-0120

(2021/12/18)

IRAK DEGRADERS AND USES THEREOF
The present invention provides compounds, compositions thereof, and methods of using the same.
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(2020/06/19)

Structure-Based Design of a Bromodomain and Extraterminal Domain (BET) Inhibitor Selective for the N-Terminal Bromodomains That Retains an Anti-inflammatory and Antiproliferative Phenotype
The bromodomain and extraterminal domain (BET) family of epigenetic regulators comprises four proteins (BRD2, BRD3, BRD4, BRDT), each containing tandem bromodomains. To date, small molecule inhibitors of these proteins typically bind all eight bromodomains of the family with similar affinity, resulting in a diverse range of biological effects. To enable further understanding of the broad phenotype characteristic of pan-BET inhibition, the development of inhibitors selective for individual, or sets of, bromodomains within the family is required. In this regard, we report the discovery of a potent probe molecule possessing up to 150-fold selectivity for the N-terminal bromodomains (BD1s) over the C-terminal bromodomains (BD2s) of the BETs. Guided by structural information, a specific amino acid difference between BD1 and BD2 domains was targeted for selective interaction with chemical functionality appended to the previously developed I-BET151 scaffold. Data presented herein demonstrate that selective inhibition of BD1 domains is sufficient to drive anti-inflammatory and antiproliferative effects.
Wellaway, Christopher R.,Bamborough, Paul,Bernard, Sharon G.,Chung, Chun-Wa,Craggs, Peter D.,Cutler, Leanne,Demont, Emmanuel H.,Evans, John P.,Gordon, Laurie,Karamshi, Bhumika,Lewis, Antonia J.,Lindon, Matthew J.,Mitchell, Darren J.,Rioja, Inmaculada,Soden, Peter E.,Taylor, Simon,Watson, Robert J.,Willis, Rob,Woolven, James M.,Wyspiańska, Beata S.,Kerr, William J.,Prinjha, Rab K.
p. 9020 - 9044
(2020/08/24)

NEW HETEROCYCLIC COMPOUNDS AS MONOACYLGLYCEROL LIPASE INHIBITORS
The invention provides new heterocyclic compounds having the general formula (I) wherein A, L, X, m, n, R1 and R2 are as described herein, compositions including the compounds, processes of manufacturing the compounds, methods of using the compounds and methods of determining the monoacylglycerol lipase (MAGL) inhibitory activity of the compounds.
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Page/Page column 64; 163

(2020/03/05)

NEW HETEROCYCLIC COMPOUNDS AS MONOACYLGLYCEROL LIPASE INHIBITORS
The invention provides new heterocyclic compounds having the general formula (I) wherein A, L, X, m, n, R1 and R2 are as described herein, compositions including the compounds, processes of manufacturing the compounds and methods of using the compounds.
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Page/Page column 171; 172

(2020/03/05)

N-ACYL-{4-[(4-ARYL-PHENYL)SULFONYLMETHYL]PIPERIDINE} COMPOUNDS AND THEIR THERAPEUTIC USE
The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to certain N-acyl-{4-[(4-aryl- phenyl)sulfonylmethyl]piperidine} compounds of the following formula (collectively referred to
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Page/Page column 123; 124

(2020/10/28)

Maximizing ER-α Degradation Maximizes Activity in a Tamoxifen-Resistant Breast Cancer Model: Identification of GDC-0927
The further optimization of ER-α degradation efficacy of a series of ER modulators by refining side-chain substitution led to efficacious selective estrogen receptor degraders (SERDs). A fluoromethyl azetidine group was found to be preferred and resulted
Kahraman, Mehmet,Govek, Steven P.,Nagasawa, Johnny Y.,Lai, Andiliy,Bonnefous, Celine,Douglas, Karensa,Sensintaffar, John,Liu, Nhin,Lee, Kyoungjin,Aparicio, Anna,Kaufman, Josh,Qian, Jing,Shao, Gang,Prudente, Rene,Joseph, James D.,Darimont, Beatrice,Brigham, Daniel,Heyman, Richard,Rix, Peter J.,Hager, Jeffrey H.,Smith, Nicholas D.
supporting information
p. 50 - 55
(2019/01/15)

PYRIDONE COMPOUND AS C-MET INHIBITOR
Disclosed in the present invention is a type of pyridone compounds as c-met inhibitors, and specifically disclosed is a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof.
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Paragraph 0136-0138

(2019/08/27)

CDK4/6 INHIBITORS AND USE THEREOF
The present disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt, a solvate, a stereoisomer, or tautomer thereof, a pharmaceutical composition comprising a compound of formula (A) or formula (B), and any subgenera thereof, and use of said compounds and compositions thereof, wherein R1, R2, R3a, R3b, R5, R6, X1, X2, Y and n are described herein.
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Paragraph 688-690

(2019/03/05)

Benzo [d] [1, 3] oxathiol, benzo [d] [1, 3] benzo [d] [1, 3] oxathiol 3 - oxide or 3, 3 - dioxide compounds and G protein-coupled receptor 119 oxathiol action of number as method/use
There are provided compounds containing benzo[d][1,3]oxathiole, benzo[d][1,3]oxathiole 3-oxide, and benzo[d][1,3]oxathiole 3,3-dioxide, as well as uses/methods related thereto, including treatment of diseases and condition associated with GPR119 dysregulation, Type 2 diabetes mellitus, and related metabolic disorders.
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Paragraph 1325-1327

(2019/04/02)

COMPOUNDS CONTAINING POLYSUBSTITUTED BENZO[D][1,3]OXATHIOLE, BENZO[D][1,3]OXATHIOLE 3-OXIDE OR BENZO[D][1,3]OXATHIOLE 3,3-DIOXIDE AND METHODS/USES THEREOF AS AGONISTS OF G PROTEIN-COUPLED RECEPTOR 119
There are provided compounds having formula (I), in which: X1 and X2 are selected from certain combinations of O, S, SO and SO2; X3 is selected from CH, CF and N; X4 is selected from CH and N; X6, X6' and X6'' are selected from H, halogen, and certain alkyl, haloalkyl, alkoxy, hydroxyalkyl, and amide groups; X7 and X7' are selected from H, halogen, and certain alkyl, haloalkyl, alkoxy, hydroxyalkyl, aminoalkyl and amide groups, or both X7 and X7' together form a cycloalkyl or heterocycle; and A is selected from certain optionally substituted, alkoxy, piperazinyl and pyrrolidinyl groups. Also provided are compositions comprising these compounds, as well as uses/methods related thereto, including treatment of diseases and conditions associated with GPR119 dysregulation, Type 2 diabetes mellitus, and related metabolic disorders. (I)
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Paragraph 0597-0598

(2019/07/04)

4 - Amino - pyrimidine and nitrogen heterocyclic derivatives and its preparation and use (by machine translation)
The invention belongs to the field of biological chemistry, and in particular relates to 4 - amino - pyrimidine and nitrogen heterocyclic derivatives and its preparation and use. The present invention provides a 4 - amino - pyrimidine and nitrogen heteroc
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Paragraph 0218-0222

(2019/10/02)

Targeting Serotonin 2A and Adrenergic α1 Receptors for Ocular Antihypertensive Agents: Discovery of 3,4-Dihydropyrazino[1,2-b]indazol-1(2H)-one Derivatives
Glaucoma affects millions of people worldwide and causes optic nerve damage and blindness. The elevation of the intraocular pressure (IOP) is the main risk factor associated with this pathology, and decreasing IOP is the key therapeutic target of current pharmacological treatments. As potential ocular hypotensive agents, we studied compounds that act on two receptors (serotonin 2A and adrenergic α1) linked to the regulation of aqueous humour dynamics. Herein we describe the design, synthesis, and pharmacological profiling of a series of novel bicyclic and tricyclic N2-alkyl-indazole-amide derivatives. This study identified a 3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one derivative with potent serotonin 2A receptor antagonism, >100-fold selectivity over other serotonin subtype receptors, and high affinity for the α1 receptor. Moreover, upon local administration, this compound showed superior ocular hypotensive action in vivo relative to the clinically used reference compound timolol.
Furlotti, Guido,Alisi, Maria Alessandra,Cazzolla, Nicola,Ceccacci, Francesca,Garrone, Beatrice,Gasperi, Tecla,La Bella, Angela,Leonelli, Francesca,Loreto, Maria Antonietta,Magarò, Gabriele,Mangano, Giorgina,Bettolo, Rinaldo Marini,Masini, Emanuela,Miceli, Martina,Migneco, Luisa Maria,Vitiello, Marco
p. 1597 - 1607
(2018/07/30)

Antimalarial agents against both sexual and asexual parasites stages: structure-activity relationships and biological studies of the Malaria Box compound 1-[5-(4-bromo-2-chlorophenyl)furan-2-yl]-N-[(piperidin-4-yl)methyl]methanamine (MMV019918) and analogues
Therapies addressing multiple stages of Plasmodium falciparum life cycle are highly desirable for implementing malaria elimination strategies. MMV019918 (1, 1-[5-(4-bromo-2-chlorophenyl)furan-2-yl]-N-[(piperidin-4-yl)methyl]methanamine) was selected from the MMV Malaria Box for its dual activity against both asexual stages and gametocytes. In-depth structure-activity relationship studies and cytotoxicity evaluation led to the selection of 25 for further biological investigation. The potential transmission blocking activity of 25 versus P. falciparum was confirmed through the standard membrane-feeding assay. Both 1 and 25 significantly prolonged atrioventricular conduction time in Langendorff-isolated rat hearts, and showed inhibitory activity of Ba2+ current through Cav1.2 channels. An in silico target-fishing study suggested the enzyme phosphoethanolamine methyltransferase (PfPMT) as a potential target. However, compound activity against PfPMT did not track with the antiplasmodial activity, suggesting the latter activity relies on a different molecular target. Nevertheless, 25 showed interesting activity against PfPMT, which could be an important starting point for the identification of more potent inhibitors active against both sexual and asexual stages of the parasite.
Vallone, Alessandra,D'Alessandro, Sarah,Brogi, Simone,Brindisi, Margherita,Chemi, Giulia,Alfano, Gloria,Lamponi, Stefania,Lee, Soon Goo,Jez, Joseph M.,Koolen, Karin J.M.,Dechering, Koen J.,Saponara, Simona,Fusi, Fabio,Gorelli, Beatrice,Taramelli, Donatella,Parapini, Silvia,Caldelari, Reto,Campiani, Giuseppe,Gemma, Sandra,Butini, Stefania
p. 698 - 718
(2018/03/24)

Structure Guided Lead Generation toward Nonchiral M. tuberculosis Thymidylate Kinase Inhibitors
In recent years, thymidylate kinase (TMPK), an enzyme indispensable for bacterial DNA biosynthesis, has been pursued for the development of new antibacterial agents including against Mycobacterium tuberculosis, the causative agent for the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous efforts toward the exploration of novel and potent Mycobacterium tuberculosis TMPK (MtTMPK) inhibitors, and reported here the design of a novel series of non-nucleoside inhibitors of MtTMPK. The inhibitors display hitherto unexplored interactions in the active site of MtTMPK, offering new insights into structure-activity relationships. To investigate the discrepancy between enzyme inhibitory activity and the whole-cell activity, experiments with efflux pump inhibitors and efflux pump knockout mutants were performed. The minimum inhibitory concentrations of particular inhibitors increased significantly when determined for the efflux pump mmr knockout mutant, which partly explains the observed dissonance.
Song, Lijun,Merceron, Romain,Gracia, Bego?a,Quintana, Ainhoa Lucía,Risseeuw, Martijn D. P.,Hulpia, Fabian,Cos, Paul,Aínsa, José A.,Munier-Lehmann, Hélène,Savvides, Savvas N.,Van Calenbergh, Serge
p. 2753 - 2775
(2018/04/23)

Design, synthesis and biological evaluation of 7H-pyrrolo[2,3-d]pyrimidin-4-amine derivatives as selective Btk inhibitors with improved pharmacokinetic properties for the treatment of rheumatoid arthritis
Bruton's tyrosine kinase (Btk) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) and Fcγ receptor (FcR) signaling pathways, which makes it a uniquely attractive target for the treatment of autoimmune diseases, such as rheumatoid arthritis (RA). We reported a series of compounds bearing 7H-pyrrolo [2,3-d]pyrimidin-4-amine scaffold that potently inhibited Btk in vitro. Analysis of the structure-activity relationships (SAR) and drug-like profiles led to the discovery of the optimal compound B16. B16 preferentially inhibited Btk (IC50 = 21.70 ± 0.82 nM) over closely related kinases with moderate selectivity. Cell-based tests also confirmed that B16 significantly inhibited Btk Y223 auto-phosphorylation and PLCγ2 Y1217 phosphorylation. MTT revealed that B16 displayed weak suppression against normal LO2, HEK293 and THP-1 cell lines with IC50 values over 30 μM. Moreover, B16 showed very weak potential to block the hERG channel (IC50 = 11.10 μM) in comparison to ibrutinib (IC50 = 0.97 μM). Owing to its favorable physicochemical properties (ClogP = 2.53, aqueous solubility ≈ 0.1 mg/mL), pharmacokinetic profiles (F = 49.15%, t1/2 = 7.02 h) and reasonable CYP450 profile, B16 exhibited potent anti-arthritis activity and similar efficacy to ibrutinib in reducing paw thickness in CIA mice. In conclusion, B16 is a potent, selective and durable inhibitor of Btk and has the potential to a safe and efficacious treatment for arthritis.
He, Linhong,Pei, Heying,Zhang, Chufeng,Shao, Mingfeng,Li, Dan,Tang, Mingli,Wang, Taijing,Chen, Xiaoxin,Xiang, Mingli,Chen, Lijuan
p. 96 - 112
(2018/01/10)

Saturated Heterocyclic Aminosulfonyl Fluorides: New Scaffolds for Protecting-Group-Free Synthesis of Sulfonamides
Cyclic saturated aminosulfonyl fluorides were synthesized as their HCl salts. The compounds were found to be stable upon storage and could be used for the protecting-group-free synthesis of sulfonamides. In the presence of the ?SO2F group, the nitrogen atom could be modified by means of acylation, arylation, or reductive amination to give products that have high potential for the synthesis of bioactive compounds.
Zhersh, Sergey A.,Blahun, Oleksandr P.,Sadkova, Iryna V.,Tolmachev, Andrey A.,Moroz, Yurii S.,Mykhailiuk, Pavel K.
supporting information
p. 8343 - 8349
(2018/06/04)

CYCLOHEXENE DERIVATIVE, PREPARATION METHOD THEREFOR, AND PHARMACEUTICAL COMPOSITION FOR PREVENTING OR TREATING METABOLIC DISEASES, CONTAINING SAME AS ACTIVE INGREDIENT
The present invention relates to: a cyclohexene derivative; a preparation method therefor; and a pharmaceutical composition for preventing or treating metabolic diseases, containing the same as an active ingredient. The cyclohexene derivative according to the present invention increases the intracellular activity of cyclic adenosine monophosphate (cAMP) by activating G protein-coupled receptor 119 (GPR-119) and simultaneously exhibits weight loss and hypoglycemic effects by inducing the release of glucagon-like peptide-1 (GLP-1), which is a neuroendocrine protein, and thus can be useful as a pharmaceutical composition for preventing or treating metabolic diseases such as obesity, type 1 diabetes, type 2 diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia and syndrome X.
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Paragraph 0086; 0087; 0088; 0095; 0096; 0097

(2017/03/21)

CYCLOHEXENE DERIVATIVE, PREPARATION METHOD THEREOF, AND PHARMACEUTICAL COMPOSITION FOR PREVENTING OR TREATING METABOLIC DISEASE COMPRISING THE SAME AS ACTIVE INGREDIENT
The present invention relates to: a cyclohexene derivative; a preparation method thereof; and a pharmaceutical composition for preventing or treating metabolic disease comprising the same as an active ingredient. The cyclohexene derivative according to the present invention increases the intracellular activity of cyclic adenosine monophosphate (cAMP) by activating G protein-coupled receptor 119 (GPR-119) and simultaneously exhibits weight loss and hypoglycemic effects by inducing the release of glucagon-like peptide-1 (GLP-1), which is a neuroendocrine protein, and thus can be useful as a pharmaceutical composition for preventing or treating metabolic diseases such as obesity, type 1 diabetes, type 2 diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia and syndrome X.
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Page/Page column 651; 652; 653; 654; 663; 664; 665; 666

(2017/05/19)

Optimization of a novel series of potent and orally bioavailable GPR119 agonists
We describe the discovery and optimization of a novel series of furo[3,2-d]pyrimidines as G protein-coupled receptor 119 agonists. Agonistic activity of 4 (EC50?=?129?nM) was improved by replacing the intramolecular hydrogen bond between the fluorine atom and the aniline hydrogen in the head moiety with a covalent C-C bond to enhance conformational restriction, which consequently gave a lead compound 12 (EC50?=?53?nM). Optimized compound 26, which was identified by the further optimization of 12, exhibited potent activity (EC50?=?42?nM) with improved clearance in liver microsomes and induced a 33% reduction in blood glucose area under the curve at a dose of 10?mg/kg in an oral glucose tolerance test in C57BL/6N mice.
Koshizawa, Tomoaki,Morimoto, Toshiharu,Watanabe, Gen,Watanabe, Toshiaki,Yamasaki, Nao,Sawada, Yoshikazu,Fukuda, Tomoaki,Okuda, Ayumu,Shibuya, Kimiyuki,Ohgiya, Tadaaki
p. 3249 - 3253
(2017/07/07)

COMPOUNDS FOR REACTIVATION OF ACETYLCHOLINESTERASE AND RELATED COMPOSITIONS METHODS AND SYSTEMS
Described herein are oxime compounds capable of inactivating a nerve agent, blood brain barrier (BBB)-penetration, and/or reactivation of nerve agent-inhibited acetylcholinesterase (AChE) and related methods, systems and compositions for inactivation of one or more nerve agents, therapeutic and/or prophylactic treatment of an individual, and/or decomposition of nerve agent for decontamination.
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(2017/12/27)

NOVEL COMPOUNDS AS INHIBITORS OF DNA METHYLTRANSFERASES
It relates to the compounds of formula (I), or their pharmaceutically or veterinary acceptable salts, or their stereoisomers or mixtures thereof, wherein A, R1, R2, and R3 are as defined herein, which are inhibitors of one or more DNMTs selected from the group consisting of DNMT1, DNMT3A and DNMT3B. It also relates to pharmaceutical or veterinary compositions containing them, and to their use in medicine, in particular in the treatment and/or prevention of cancer, fibrosis and/or immunomodulation.
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Page/Page column 56

(2017/08/01)

AMINE-SUBSTITUTED ARYL OR HETEROARYL COMPOUNDS AS EHMT1 AND EHMT2 INHIBITORS
The present disclosure relates to amine-substituted aryl or heteroaryl compounds. The present disclosure also relates to pharmaceutical compositions containing these compounds and methods of treating a disorder (e.g., sickle cell anemia) via inhibition of a methyltransferase enzyme selected from EHMT1 and EHMT2, by administering an amine-substituted aryl or heteroaryl compound disclosed herein or a pharmaceutical composition thereof to subjects in need thereof. The present disclosure also relates to the use of such compounds for research or other non-therapeutic purposes.
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Paragraph 01184-01187

(2017/11/10)

POLYFLUORINATED COMPOUNDS ACTING AS BRUTON TYROSINE KINASE INHIBITORS
Described herein is a novel series of multi-fluoro-substituted pyrazolopyrimidine compounds or salts thereof. These compounds are Bruton's tyrosine kinase (BTK) inhibitors. These compounds may possess better BTK inhibition selectivity and pharmacokinetic properties. Disclosed herein are the synthesis methods of these compounds. Disclosed herein are novel synthesis methods of the multi-fluoro-substituted benzophenone and substituted phenoxy benzene. Also disclosed are pharmaceutical compositions comprising the BTK inhibitors described herein. The present invention also relates to pharmaceutical formulations comprising the compounds described herein as active ingredients. The present invention also includes the therapeutic methods by administering the BTK inhibitors and their formulations to treat and inhibit autoimmune disease, hypersensitivity disease, inflammatory diseases and cancer.
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(2016/08/17)

Exploring Basic Tail Modifications of Coumarin-Based Dual Acetylcholinesterase-Monoamine Oxidase B Inhibitors: Identification of Water-Soluble, Brain-Permeant Neuroprotective Multitarget Agents
Aiming at modulating two key enzymatic targets for Alzheimer's disease (AD), i.e., acetylcholinesterase (AChE) and monoamine oxidase B (MAO B), a series of multitarget ligands was properly designed by linking the 3,4-dimethylcoumarin scaffold to 1,3- and 1,4-substituted piperidine moieties, thus modulating the basicity to improve the hydrophilic/lipophilic balance. After in vitro enzymatic inhibition assays, multipotent inhibitors showing potencies in the nanomolar and in the low micromolar range for hMAO B and eeAChE, respectively, were prioritized and evaluated in human SH-SY5Y cell-based models for their cytotoxicity and neuroprotective effect against oxidative toxins (H2O2, rotenone, and oligomycin-A). The present study led to the identification of a promising multitarget hit compound (5b) exhibiting high hMAO B inhibitory activity (IC50 = 30 nM) and good MAO B/A selectivity (selectivity index, SI = 94) along with a micromolar eeAChE inhibition (IC50 = 1.03 μM). Moreover, 5b behaves as a water-soluble, brain-permeant neuroprotective agent against oxidative insults without interacting with P-gp efflux system.
Pisani, Leonardo,Farina, Roberta,Catto, Marco,Iacobazzi, Rosa Maria,Nicolotti, Orazio,Cellamare, Saverio,Mangiatordi, Giuseppe Felice,Denora, Nunzio,Soto-Otero, Ramon,Siragusa, Lydia,Altomare, Cosimo Damiano,Carotti, Angelo
p. 6791 - 6806
(2016/08/05)

IMIDAZO[1,2-b]PYRIDAZINE DERIVATIVES AS KINASE INHIBITORS
The present invention is intended to provide a compound or a pharmacologically acceptable salt thereof which is useful in the treatment of a tumor through its ROS1 kinase enzyme activity inhibitory effect and NTRK kinase enzyme inhibitory effect. The present invention provides a compound having an imidazo[1,2-b]pyridazine structure represented by the general formula (I) or a pharmacologically acceptable salt thereof, and a pharmaceutical composition comprising the compound. In the formula, R1, G, T, Y1, Y2, Y3, and Y4 are as defined herein.
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Paragraph 0238; 0239

(2016/03/13)

PYRIMIDINE AND TRIAZINE DERIVATIVES AND THEIR USE AS AXL INHIBITORS
Compounds of the general formula(I): (I) processes for the preparation of these compounds, compositions containing these compounds, and the uses of these compounds.
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Page/Page column 65

(2016/07/05)

INHIBITORS OF THE RENAL OUTER MEDULLARY POTASSIUM CHANNEL
no abstract published
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Paragraph 0161

(2016/09/26)

AMIDE DERIVATIVES FOR GPR119 AGONIST
The present invention relates to novel amide derivatives, stereoisomers thereof or pharmaceutically acceptable salts thereof; methods for preparing the compound; and pharmaceutical compositions comprising the compound. The novel amide derivatives, according to the present invention, having an effect as GPR119 agonist can be used for treatment of metabolic disorders, including diabetes mellitus (especially type II) and related disorders.
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(2015/06/11)

PIPERIDINE DERIVATIVES FOR GPR119 AGONIST
The present invention relates to novel piperidine derivatives, stereoisomers thereof or pharmaceutically acceptable salts thereof; methods for preparing the compound; and pharmaceutical compositions comprising the compound. The novel piperidine derivatives, according to the present invention, having an effect as GPR119 agonist can be used for treatment of metabolic disorders, including diabetes mellitus (especially type II) and related disorders.
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(2015/06/24)

NOVEL INDOLE DERIVATIVE COMPOUND AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
The present invention provides a novel indole derivative compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. The compound according to the present invention can selectively inhibit histone deacetylase (HDAC), and thus can be used to effectively treat a disease associated with histone deacetylase (HDAC) activity.
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(2015/07/16)

Discovery of novel 2,5-dioxoimidazolidine-based P2X7 receptor antagonists as constrained analogues of KN62
Novel 2,5-dioxoimidazolidine-based conformationally constrained analogues of KN62 (1) were developed as P2X7 receptor (P2X7R) antagonists using a rigidification strategy of the tyrosine backbone of 1. SAR analysis of the 2,5-dioxoimidazolidine scaffold indicated that piperidine substitution at the N3 position and no substitution at N1 position were preferable. Further optimization of the substituents at the piperidine nitrogen and the spacer around the skeleton resulted in several superior antagonists to 1, including 1-adamantanecarbonyl analogue 21i (IC50 = 23 nM in ethidium uptake assay; IC50 = 14 nM in IL-1β ELISA assay) and (3-CF3-4-Cl)benzoyl analogue (-)-21w (54 nM in ethidium uptake assay; 9 nM in IL-1β ELISA assay), which was more potent than the corresponding (+) isomer. Compound 21w displayed potent inhibitory activity in an ex vivo model of LTP-induced pain signaling in the spinal cord and significant anti-inflammatory activity in in vivo models of carrageenan-induced paw edema and type II collagen-induced joint arthritis.
Park, Jin-Hee,Lee, Ga-Eun,Lee, So-Deok,Hien, Tran Thi,Kim, Sujin,Yang, Jin Won,Cho, Joong-Heui,Ko, Hyojin,Lim, Sung-Chul,Kim, Yoon-Gyoon,Kang, Keon-Wook,Kim, Yong-Chul
supporting information
p. 2114 - 2134
(2015/03/30)

IMIDAZO[1,2-b]PYRIDAZINE DERIVATIVES AS KINASE INHIBITORS
The present invention is intended to provide a compound or a pharmacologically acceptable salt thereof which is useful in the treatment of a tumor through its ROS1 kinase enzyme activity inhibitory effect and NTRK kinase enzyme inhibitory effect. The present invention provides a compound having an imidazo[1,2-b]pyridazine structure represented by the general formula (I) or a pharmacologically acceptable salt thereof, and a pharmaceutical composition comprising the compound. In the formula, R1, G, T, Y1, Y2, Y3, and Y4 are as defined herein.
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Paragraph 0182-0183

(2015/02/25)

ANTIDIABETIC SUBSTITUTED HETEROARYL COMPOUNDS
The present invention relates to a compound represented by formula I: and pharmaceutically acceptable salts thereof. The compounds of formula I are agonists of G-protein coupled receptor 40 (GPR40) and may be useful in the treatment, prevention and suppression of diseases mediated by the G-protein-coupled receptor 40. The compounds of the present invention may be useful in the treatment of Type 2 diabetes mellitus, and of conditions that are often associated with this disease, including obesity and lipid disorders, such as mixed or diabetic dyslipidemia, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia.
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Page/Page column 87

(2015/07/07)

ANTIDIABETIC SUBSTITUTED HETEROARYL COMPOUNDS
The present invention relates to a compound represented by formula (I): and pharmaceutically acceptable salts thereof. The compounds of formula I are agonists of G-protein coupled receptor 40 (GPR40) and may be useful in the treatment, prevention and suppression of diseases mediated by the G-protein-coupled receptor 40. The compounds of the present invention may be useful in the treatment of Type 2 diabetes mellitus, and of conditions that are often associated with this disease, including obesity and lipid disorders, such as mixed or diabetic dyslipidemia, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia.
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Page/Page column 87

(2015/07/07)

AUTOTAXIN INHIBITORS COMPRISING A HETEROAROMATIC RING-BENZYL-AMIDE-CYCLE CORE
The present invention relates to novel compounds that are autotaxin inhibitors, processes for their preparation, pharmaceutical compositions and medicaments containing them and to their use in diseases and disorders mediated by autotaxin.
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Page/Page column 302; 303

(2015/02/02)

NOVEL COMPOUNDS AS DUAL INHIBITORS OF PHOSPHODIESTERASES AND HISTONE DEACETYLASES
It relates to certain compounds having a polycyclic structure and a hydroxamic acid moiety, wherein the polycyclic structure comprises at least three ring systems, wherein one ring system is a polycyclic ring system comprising from 2 to 4 rings; at least one ring is an aromatic ring; and wherein the structure comprises at least 3 nitrogen atoms and 1 oxygen atom. It also relates to a process for their preparation, as well as to pharmaceutical compositions containing them, and to their use in medicine, in particular in the treatment and/or prevention of neurological disorders coursing with a cognition deficit or impairment, or neurodegenerative diseases. wherein B1 is a radical selected from the group consisting of formula (A"), formula (B"), formula (C"), and formula (D"):
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Page/Page column 62

(2014/09/16)

ANTIBACTERIAL PIPERIDINYL SUBSTITUTED 3,4-DIHYDRO-1H-[1,8]NAPHTHYRIDINONES
The present invention is related to novel compounds of formula (I) that inhibit the activity of the Fab1 enzyme which are therefore useful in the treatment of bacterial infections. It further relates to pharmaceutical compositions comprising these compounds, and chemical processes for preparing these compounds.
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(2013/03/26)

NOVEL CONDENSED PYRIDINE OR CONDENSED PYRIMIDINE DERIVATIVE, AND MEDICINAL AGENT COMPRISING SAME
The present invention relates to provision of a novel compound that has an activity of promoting insulin secretion from pancreatic β cells and thus is useful as a prophylaxis and/or therapeutic agent for diseases caused by hyperglycemia such as diabetes mellitus, and the compound represented by the following formula (1): wherein one of A and B represents a nitrogen atom and the other represents a nitrogen atom or CR10, X represents an oxygen atom, a sulfur atom or —(CH2)n-N(R12)—, Y represents an oxygen atom, a sulfur atom or —N(R13)—, and R1 to R9 each represent a hydrogen atom or another substituent, or a salt thereof, or a solvate of the compound or the salt.
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(2013/05/08)

PIPERIDINE DERIVATIVES FOR G PR119 AGONIST
The present invention relates to novel piperidine derivatives, stereoisomers thereof or pharmaceutically acceptable salts thereof; methods for preparing the compound; and pharmaceutical compositions comprising the compound. The novel piperidine derivatives, according to the present invention, having an effect as GPR119 agonist can be used for treatment of metabolic disorders, including diabetes mellitus (especially type II) and related disorders
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(2014/01/08)

INHIBITORS OF THE RENAL OUTER MEDULLARY POTASSIUM CHANNEL
This invention relates to compounds having structural Formula I: and pharmaceutically acceptable salts thereof which are inhibitors of the Renal Outer Medullary Potassium (ROMK) channel (Kirl.1). The compounds of Formula I are useful as diuretics and natriuretics and therefore are useful for the therapy and prophylaxis of disorders resulting from excessive salt and water retention, including cardiovascular diseases such as hypertension and chronic and acute heart failure
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Page/Page column 46; 47

(2013/03/28)

Development of Toxoplasma gondii calcium-dependent protein kinase 1 (Tg CDPK1) inhibitors with potent anti- toxoplasma activity
Toxoplasmosis is a disease of prominent health concern that is caused by the protozoan parasite Toxoplasma gondii. Proliferation of T. gondii is dependent on its ability to invade host cells, which is mediated in part by calcium-dependent protein kinase 1 (CDPK1). We have developed ATP competitive inhibitors of TgCDPK1 that block invasion of parasites into host cells, preventing their proliferation. The presence of a unique glycine gatekeeper residue in TgCDPK1 permits selective inhibition of the parasite enzyme over human kinases. These potent TgCDPK1 inhibitors do not inhibit the growth of human cell lines and represent promising candidates as toxoplasmosis therapeutics.
Johnson, Steven M.,Murphy, Ryan C.,Geiger, Jennifer A.,Derocher, Amy E.,Zhang, Zhongsheng,Ojo, Kayode K.,Larson, Eric T.,Perera, B. Gayani K.,Dale, Edward J.,He, Panqing,Reid, Molly C.,Fox, Anna M. W.,Mueller, Natascha R.,Merritt, Ethan A.,Fan, Erkang,Parsons, Marilyn,Van Voorhis, Wesley C.,Maly, Dustin J.
p. 2416 - 2426
(2012/06/01)