- Discovery of HDAC6-Selective Inhibitor NN-390 with in Vitro Efficacy in Group 3 Medulloblastoma
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Histone deacetylase 6 (HDAC6) has been targeted in clinical studies for anticancer effects due to its role in oncogenic transformation and metastasis. Through a second-generation structure–activity relationship (SAR) study, the design, and biological eval
- Nawar, Nabanita,Bukhari, Shazreh,Adile, Ashley A.,Suk, Yujin,Manaswiyoungkul, Pimyupa,Toutah, Krimo,Olaoye, Olasunkanmi O.,Raouf, Yasir S.,Sedighi, Abootaleb,Garcha, Harsimran Kaur,Hassan, Muhammad Murtaza,Gwynne, William,Israelian, Johan,Radu, Tudor B.,Geletu, Mulu,Abdeldayem, Ayah,Gawel, Justyna M.,Cabral, Aaron D.,Venugopal, Chitra,De Araujo, Elvin D.,Singh, Sheila K.,Gunning, Patrick T.
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p. 3193 - 3217
(2022/02/16)
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- Ligand-based rational design, synthesis and evaluation of novel potential chemical chaperones for opsin
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Inherited blinding diseases retinitis pigmentosa (RP) and a subset of Leber's congenital amaurosis (LCA) are caused by the misfolding and mistrafficking of rhodopsin molecules, which aggregate and accumulate in the endoplasmic reticulum (ER), leading to photoreceptor cell death. One potential therapeutic strategy to prevent the loss of photoreceptors in these conditions is to identify opsin-binding compounds that act as chemical chaperones for opsin, aiding its proper folding and trafficking to the outer cell membrane. Aiming to identify novel compounds with such effect, a rational ligand-based approach was applied to the structure of the visual pigment chromophore, 11-cis-retinal, and its locked analogue 11-cis-6mr-retinal. Following molecular docking studies on the main chromophore binding site of rhodopsin, 49 novel compounds were synthesized according to optimized one-to seven-step synthetic routes. These agents were evaluated for their ability to compete for the chromophore binding site of opsin, and their capacity to increase the trafficking of the P23H opsin mutant from the ER to the cell membrane. Different new molecules displayed an effect in at least one assay, acting either as chemical chaperones or as stabilizers of the 9-cis-retinal-rhodopsin complex. These compounds could provide the basis to develop novel therapeutics for RP and LCA.
- Bassetto, Marcella,Brancale, Andrea,Pasqualetto, Gaia,Pileggi, Elisa,Rozanowska, Malgorzata,Schepelmann, Martin,Varricchio, Carmine
-
supporting information
(2021/09/24)
-
- SUBSTITUTED PYRAZOLE COMPOUNDS AS TOLL RECEPTOR INHIBITORS
-
Disclosed are compounds of Formula (I) N-oxides, or salts thereof, wherein G, A, R1, and R5 are defined herein. Also disclosed are methods of using such compounds as inhibitors of signaling through Toll-like receptor 7, or 8, or 9, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating inflammatory and autoimmune diseases.
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Page/Page column 146
(2021/05/07)
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- COMPOUNDS FOR TREATMENT OF PD-L1 DISEASES
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Compounds are provided that are useful as immunomodulators. The compounds have the Formula (I) including stereoisomers and pharmaceutically acceptable salts thereof, wherein R1a, R1b, R1c, R1d, R2a, R2b, R3, R3a, R4, R5, R6, R7, R8 and the subscript n are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.
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Paragraph 0132; 0133
(2021/01/21)
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- PYRROLO[2,3-B]PYRIDINES AS HPK1 INHIBITOR AND USES THEREOF
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Disclosed herein is a compound of Formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions comprising thereof. Also disclosed is a method of treating HPK1 related disorders or diseases by using the compound disclosed herein.
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Page/Page column 21; 25
(2020/06/10)
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- NAPHTHYRIDINE DERIVATIVES AS PRC2 INHIBITORS
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Disclosed are compounds of formula (I) or (II) that inhibit Polycomb Repressive Complex 2 (PRC2) activity. In particular, the present invention relates to compounds, pharmaceutical compositions and methods of use, such as methods of treating cancer using the compounds and pharmaceutical compositions of the present invention.
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Paragraph 0385-0386
(2020/11/03)
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- IMIDAZO[1,2-C]PYRIMIDINE DERIVATIVES AS PRC2 INHIBITORS FOR TREATING CANCER
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Disclosed are compounds that inhibit Polycomb Repressive Complex 2 (PRC2) activity. In particular, disclosed are compounds of Formula (I) and pharmaceutical compositions thereof, and methods of using the compounds and pharmaceutical compositions in, for example, methods of treating cancer.
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Paragraph 0326-0327
(2020/12/29)
-
- GPR40 receptor stimulant, and preparation method, pharmaceutical composition and application thereof
-
The invention discloses a GPR40 receptor stimulant, and a preparation method, a pharmaceutical composition and application thereof. The invention particularly discloses a GPR40 receptor stimulant shown in general formula (I) and pharmacologically acceptable salt thereof, a preparation process of the compound, a pharmaceutical composition containing the compound of general formula (I), and application of the compound and the pharmaceutical composition in anti-diabetes.
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Paragraph 0163-0165; 0181-0184
(2019/10/15)
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- THIAZOLE DERIVATIVE AND APPLICATIONS THEREOF
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Disclosed in the present invention are a new thiazole compound, particularly a compound represented by formula (I), a pharmaceutical composition thereof and applications thereof in the preparation of drugs for the treatment of diseases related to herpes simplex viruses.
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Paragraph 0132; 0133
(2020/01/02)
-
- M-DIHYDROXYBENZENE DERIVATIVE CRYSTAL AND SALT, AND MANUFACTURING METHOD THEREOF
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Provided are a crystal and salt of an m-dihydroxybenzene derivative represented by formula (I), a manufacturing method thereof, and an application of the crystal in preparing a pharmaceutical product for treating a HSP90-mediated disease.
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-
-
- Azacyclic derivative as well as preparation method and medical use thereof
-
The invention relates to an azacyclic derivative as well as a preparation method and medical use thereof and particularly relates to an azacyclic derivative represented by a general formula (I) (shownin the description), a preparation method thereof, a pharmaceutical composition containing the derivative and use of the derivative as an SMO antagonist, particularly in the treatment of diseases such as cancer related to Hedgehog signal channels. The definitions of groups in the general formula (I) are same as the definitions in the description.
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-
Paragraph 0338; 0339; 0340; 0341
(2019/02/04)
-
- PRC2 INHIBITORS
-
The present invention relates to compounds that inhibit Polycomb Repressive Complex 2 (PRC2) activity. In particular, the present invention relates to compounds, pharmaceutical compositions and methods of use, such as methods of treating cancer using the compounds and pharmaceutical compositions of the present invention. (Formula (I))
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Paragraph 0335-0336
(2019/08/26)
-
- Design, synthesis and biological evaluation of a series of novel GPR40 agonists containing nitrogen heterocyclic rings
-
A novel series of GPR40 agonists is designed by introducing nitrogen-containing heterocyclic ring at the terminal phenyl ring of TAK-875 with the aim of decreasing its lipophilicity. Three different β-substituted phenylpropionic acids were investigated as the acidic components. A total of 34 compounds have been synthesized, among which, compound 30 exhibited comparable GPR40 agonistic activity in vitro with TAK-875 and relatively lower lipophilicity through calculation (30, EC50 = 1.2 μM, cLogP = 1.3; TAK-875: EC50 = 5.1 μM, cLogP = 3.4). Moreover, compound 30 was able to enhance the insulin secretion of primary islets isolated from normal ICR mice and showed no obvious inhibition against cytochromes P450 in vitro. In vivo, compound 30 exhibited efficacy in oral glucose tolerance test (oGTT) in normal ICR mice.
- Sun, Zhaozhu,Zhou, Tian,Pan, Xuan,Yang, Ying,Huan, Yi,Xiao, Zhiyan,Shen, Zhufang,Liu, Zhanzhu
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p. 3050 - 3056
(2018/08/11)
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- Structure–Activity Relationship Studies on (R)-PFI-2 Analogues as Inhibitors of Histone Lysine Methyltransferase SETD7
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SETD7 is a histone H3K4 lysine methyltransferase involved in human gene regulation. Aberrant expression of SETD7 has been associated with various diseases, including cancer. Therefore, SETD7 is considered a good target for the development of new epigenetic drugs. To date, few selective small-molecule inhibitors have been reported that target SETD7, the most potent being (R)-PFI-2. Herein we report structure–activity relationship studies on (R)-PFI-2 and its analogues. A library of 29 structural analogues of (R)-PFI-2 was synthesized and evaluated for inhibition of recombinantly expressed human SETD7. The key interactions were found to be a salt bridge and a hydrogen bond formed between (R)-PFI-2′s NH2+ group and SETD7′s Asp256 and His252 residue, respectively.
- Lenstra, Danny C.,Damen, Eddy,Leenders, Ruben G. G.,Blaauw, Richard H.,Rutjes, Floris P. J. T.,Wegert, Anita,Mecinovi?, Jasmin
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supporting information
p. 1405 - 1413
(2018/07/29)
-
- NOVEL TETRAHYDROISOQUINOLINES AND TERAHYDRONAPHTHYRIDINES FOR THE TREATMENT AND PROPHYLAXIS OF HEPATITIS B VIRUS INFECTION
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The present invention provides novel compounds having the general formula (I): wherein R1, R 2, R 3, U, V, W, X and Y are as described herein, compositions including the compounds and methods of using the compounds.
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Page/Page column 51; 52
(2018/05/24)
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- Substituted ring compound and its method and use thereof
-
The invention provides a substituted cyclic compound as well as a use method and application thereof. The compound is a compound as shown in a formula (I) or stereoisomers, stereomers, tautomers, nitric oxides, solvates, metabolites and pharmaceutically acceptable salts or prodrugs of the compound as shown in the formula (I). The invention further provides a medicament composition containing the compound. The compound and the medicament composition are capable of regulating the activity of protein kinase in a biological sample body and are used for protecting, treating or relieving proliferative diseases of patients. The formula (I) is as shown in the specification.
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Paragraph 0620; 0621; 0634; 0635; 0636
(2017/08/25)
-
- Alkynyl compound and its method and use thereof
-
The invention provides a novel substituted alkynyl compound and its pharmaceutically acceptable salt and medicinal preparation, and a use of the novel substituted alkynyl compound and its pharmaceutically acceptable salt and medicinal preparation in adjustment of protein kinase activity and intercellular or intracellular signal response. The invention also relates to a pharmaceutical composition containing the novel substituted alkynyl compound and a method for treating high-proliferative diseases of mammals especially such as human by the pharmaceutical composition.
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-
Paragraph 0462; 0493; 0495; 0496
(2018/11/03)
-
- HETEROCYCLIC COMPOUND
-
The problem of the present invention is to provide a compound having a superior RORγt inhibitory action, and useful as a prophylactic or therapeutic agent for psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, uveitis, asthma, ankylopoietic spondylarthritis, systemic lupus erythematosus, chronic obstructive pulmonary disease or the like. The present invention relates to a compound represented by the formula (I): [wherein each symbol is as described in the DESCRIPTION] or a salt thereof, which has an RORγt inhibitory action, and useful as a prophylactic or therapeutic agent for psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, uveitis, asthma, ankylopoietic spondylarthritis, systemic lupus erythematosus, chronic obstructive pulmonary disease or the like.
- -
-
-
- SUBSTITUTED BICYCLIC HETEROCYCLIC COMPOUNDS
-
Disclosed are compounds of Formula (I), or a salt thereof, wherein: X is CR4 or N; Y is CR4 or N, provided that Y is N only if X is N; R1 is Formulae (A) or (B); each W is independently NR1b or O; Z is a bond or CHR1d; and R1, R2, R3, R4, L1, R1a, R1b, R1c, and n are defined herein. Also disclosed are methods of using such compounds as inhibitors of ROMK, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating cardiovascular diseases.
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Page/Page column 58
(2017/11/15)
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- BENZOLACTAM COMPOUNDS AS PROTEIN KINASE INHIBITORS
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The invention provides a compound of formula (0): or a pharmaceutically acceptable salt, N-oxide or tautomer thereof. The compounds are inhibitors of ERK 1/2 kinases and will be useful in the treatment of ERKl/2-mediated conditions. The compounds are therefore useful in therapy, in particular in the treatment of cancer.
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Page/Page column 274
(2017/08/01)
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- SUBSTITUTED TETRAHYDROISOQUINOLINE COMPOUNDS USEFUL AS GPR120 AGONISTS
-
The present invention relates to a compound represented by formula (I) and pharmaceutically acceptable salts thereof are disclosed as useful for treating or preventing diabetes, hyperlipidemia, obesity, NASH, inflammation related disorders, and related di
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Page/Page column 92; 93
(2017/12/29)
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- Benzenesulfonyl-Asymmetric Ureas and Medical Uses Thereof
-
Benzenesulfonyl-asymmetric ureas are provided for the treatment of conditions modulated by the ghrelin receptor.
- -
-
Paragraph 0210; 0211
(2017/10/10)
-
- SUBSTITUTED CYCLIC COMPOUNDS AND METHODS OF USE
-
The present invention provides novel substituted alkynyl compounds, pharmaceutical acceptable salts and formulations thereof useful in modulating the protein tyrosine kinase activity, and in modulating cellular activities such as proliferation, differentiation, apoptosis, migration and invasion. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of hyperproliferative disorders in mammals, especially humans.
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Paragraph 0240; 0244
(2014/06/24)
-
- ALKYNYL COMPOUNDS AND METHODS OF USE
-
The present invention provides novel substituted alkynyl compounds, pharmaceutical acceptable salts and formulations thereof useful in modulating the protein tyrosine kinase activity, and in modulating cellular activities such as proliferation, differentiation, apoptosis, migration and invasion. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of hyperproliferative disorders in mammals, especially humans.
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Page/Page column 61; 64
(2014/06/24)
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- SUBSTITUTED PYRIDINE DERIVATIVES AS FABI INHIBITORS
-
The present invention provides substituted pyridine derivatives of formula (I), which may be therapeutically useful as as anti-bacterial agents, more particulalrly FabI inhibitors. Formula(I) in which R1 to R5 and L have the meanings given in the specification, and pharmaceutically acceptable salts thereof that are useful in the treatment and prevention in diseases or disorder, in particular their use in diseases or disorder where there is an advantage anti-bacterial agents, more particularly FabI inhibitors. The present invention also provides methods for synthesizing and administering the FabI inhibitor compounds. The present invention also provides pharmaceutical formulations comprising at least one of the FabI inhibitor compounds together with a pharmaceutically acceptable carrier, diluent or excipient therefor.
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-
-
- THIAZOLE OR THIADIZALOE DERIVATIVES FOR USE AS SPHINGOSINE 1-PHOSPHATE 1 (S1P1) RECEPTOR AGONISTS
-
Thiazole or thiadizaloe derivatives of formula (I) or pharmaceutical salts thereof having pharmacological activity, processes for their preparation, pharmaceutical compositions containing them and their uses in the treatment of various disorders mediated
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Page/Page column 35-36
(2010/12/31)
-
- S1P1 AGONISTS COMPRISING A BICYCLIC N-CONTAINING RING
-
The present invention relates to novel compounds of formula (I) having S1P1 agonist activity, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of various disorders.
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Page/Page column 94-95
(2010/12/31)
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- MODULATORS OF THE HISTAMINE H3 RECEPTOR USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO
-
Amide derivatives of Formula (Ia) and pharmaceutical compositions thereof that modulate the activity of the histamine H3 receptor. Compounds of the present invention and pharmaceutical compositions thereof are directed to methods useful in the treatment of histamine H3-associated disorders, such as cognitive disorders, epilepsy, brain trauma, depression, obesity, disorders of sleep and wakefulness such as excessive daytime sleepiness, narcolepsy, shift-work sleep disorder, drowsiness as a side effect from a medication, maintenance of vigilance to aid in the completion of tasks and the like, cataplexy, hypersomnia, somnolence syndrome, jet lag, sleep apnea and the like, attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, allergic rhinitis, nasal congestion, dementia, Alzheimer's disease, pain and the like.
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Page/Page column 71
(2009/10/18)
-
- Certain pyrazoline derivatives with kinase inhibitory activity
-
The present invention provides certain pyrazoline compounds useful as inhibitors of protein kinases. The invention also provides pharmaceutical compositions and methods of using the compositions in the treatment of various diseases.
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Page/Page column 101; 102
(2008/12/06)
-
- 1,2-CYCL0HEXANE DICARBOXAMIDES AS CATHEPSIN INHIBITORS
-
The present invention relates to compounds and compositions for treating diseases associated with cysteine protease activity. The compounds are reversible inhibitors of cysteine proteases, including cathepsins B, K, C, F, H, L, O, S, W and X. Of particular interest are diseases associated with Cathepsin K.
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Page/Page column 51
(2009/03/07)
-
- NOVEL COMPOUNDS
-
The invention provides compounds of formula (I): wherein R1, R2, A, A1 and B are as defined in the specification; processes for their preparation; pharmaceutical compositions containing them; a process for preparing the ph
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Page/Page column 17; 24-25
(2010/11/08)
-
- NOVEL HYDANTOIN DERIVATIVES AS METALLOPROTEINASE INHIBITORS
-
The invention provides compounds of formula (I): wherein R1, R2, A, A1 and B are as defined in the specification; processes for their preparation; pharmaceutical compositions containing them; a process for preparing the ph
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Page/Page column 16; 24
(2010/11/08)
-