- Discovery and biological profile of isoindolinone derivatives as novel metabotropic glutamate receptor 1 antagonists: A potential treatment for psychotic disorders
-
We describe here the discovery and biological profile of a series of isoindolinone derivatives as developed mGluR1 antagonists. Our combined strategy of rapid parallel synthesis and conventional medicinal optimization successfully led to N-cyclopropyl 22 and N-isopropyl isoindolinone analogs 21 and 23 with improved in vivo DMPK profiles. Moreover the most advanced analog 23 showed an oral antipsychotic-like effect at a dose of 1 mg/kg in an animal model.
- Ito, Satoru,Hirata, Yukari,Nagatomi, Yasushi,Satoh, Atsushi,Suzuki, Gentaroh,Kimura, Toshifumi,Satow, Akio,Maehara, Shunsuke,Hikichi, Hirohiko,Hata, Mikiko,Ohta, Hisashi,Kawamoto, Hiroshi
-
-
Read Online
- CC-90009: A Cereblon E3 Ligase Modulating Drug That Promotes Selective Degradation of GSPT1 for the Treatment of Acute Myeloid Leukemia
-
Acute myeloid leukemia (AML) is marked by significant unmet clinical need due to both poor survival and high relapse rates where long-term disease control for most patients with relapsed or refractory AML remain dismal. Inspired to bring novel therapeutic options to these patients, we envisioned protein degradation as a potential therapeutic approach for the treatment of AML. Following this course, we discovered and pioneered a novel mechanism of action which culminated in the discovery of CC-90009. CC-90009 represents a novel protein degrader and the first cereblon E3 ligase modulating drug to enter clinical development that specifically targets GSPT1 (G1 to S phase transition 1) for proteasomal degradation. This manuscript briefly summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and efficacy data for CC-90009, which is currently in phase 1 clinical development.
- Hansen, Joshua D.,Correa, Matthew,Alexander, Matt,Nagy, Mark,Huang, Dehua,Sapienza, John,Lu, Gang,Lebrun, Laurie A.,Cathers, Brian E.,Zhang, Weihong,Tang, Yang,Ammirante, Massimo,Narla, Rama K.,Piccotti, Joseph R.,Pourdehnad, Michael,Lopez-Girona, Antonia
-
p. 1835 - 1843
(2021/03/09)
-
- PROCESSES FOR PREPARING 2-(4-CHLOROPHENYL)-N-((2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-5-YL)METHYL)-2,2-DIFLUOROACETAMIDE
-
Provided herein are processes for preparing 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide.
- -
-
-
- Br?nsted Acid Catalyzed Dearomatization by Intramolecular Hydroalkoxylation/Claisen Rearrangement: Diastereo- and Enantioselective Synthesis of Spirolactams
-
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
-
supporting information
p. 27164 - 27170
(2021/11/22)
-
- PFKFB3 INHIBITORS AND THEIR USES
-
This disclosure relates to new phthalimide and isoindolinone derivatives and other PFKFB3 inhibitors for use in the treatment of diseases. The invention further relates to pharmaceutical compositions containing such PFKFB3 inhibitors, methods of preparation thereof, methods for their use as therapeutic agents, and methods of preparation of a medicament for use in therapy, as well as kits and other inventiions comprising such PFKFB3 inhibitors. These PFKFB3 inhibitors are useful for the treatment and prophylaxis of cancer, neurodegenerative diseases, autoimmune diseases, inflammatory disorders, multiple sclerosis, metabolic diseases, inhibition of angiogenesis and other diseases and conditions, where the modulation of PFKFB3 and/or PFKFB4 has beneficial effect as well as neuroprotection.
- -
-
Page/Page column 195-196
(2020/05/21)
-
- MONO HALOGEN OR METHYL-SUBSTITUTED 5-HT2B ANTAGONISTS WITH INCREASED ACTIVITY
-
Disclose herein are mono halogen or methyl-substituted 5-HT 2B antagonist compounds, which have been found with increased binding activity to 5-HT 2B receptor due to the substitution of halogen or methyl, and the method of using the compounds of treating or preventing a disorder mediated by 5-HT 2B.
- -
-
Paragraph 0048; 0062
(2020/05/13)
-
- Aminopyrazine/pyridine compound and preparation method and application thereof
-
The invention discloses an aminopyrazine/pyridine compound and a preparation method and application thereof. Particularly, a pyrazine/pyridylamine compound shown as a general formula I, or pharmaceutically acceptable salt thereof, or enantiomer, diastereoisomer, tautomer, solvate, polymorphic substance or prodrug thereof, a preparation method thereof and application in pharmacy are disclosed, andthe definition of each group is shown in the specification.
- -
-
Paragraph 0150-0152
(2020/05/05)
-
- Degradable hydrogel under physiological conditions
-
The present invention discloses a hydrogel that can be degraded under physiological conditions. The hydrogel includes at least one backbone moiety and an optional crosslinking moiety, and biodegradable linkers connecting backbone moieties and crosslinking moieties can be degraded by intramolecular cyclization.
- -
-
Paragraph 0410; 0413
(2020/09/09)
-
- BENZAZEPINE DERIVATIVE, PREPARATION METHOD, PHARMACEUTICAL COMPOSITION AND USE THEREOF
-
Disclosed are a benzazepine derivative, a preparation method, a pharmaceutical composition and the use thereof. A compound as shown in formula (I) of the present invention, and an isomer, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof have the following structure. The benzazepine derivative of the present invention has a good regulation effect on the TLR family and the related signalling pathway, and in particular, has a good regulation effect on TLR8, can effectively treat, relieve and/or prevent various diseases mediated by TLR family and the TLR-related signalling pathway, and in particular, can effectively treat, relieve and/or prevent various diseases mediated by TLR8, such as cancers, autoimmune diseases, infections, inflammations, transplantation rejections, graft-versus-host diseases, etc.
- -
-
-
- IRAK DEGRADERS AND USES THEREOF
-
The present invention provides compounds, compositions thereof, and methods of using the same.
- -
-
Paragraph 3097; 3098
(2019/07/10)
-
- Identification of novel uracil derivatives incorporating benzoic acid moieties as highly potent Dipeptidyl Peptidase-IV inhibitors
-
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
-
p. 644 - 654
(2019/01/14)
-
- Rapid generation of novel benzoic acid–based xanthine derivatives as highly potent, selective and long acting DPP-4 inhibitors: Scaffold-hopping and prodrug study
-
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
-
p. 509 - 523
(2019/07/25)
-
- Protein Degradation via CRL4CRBN Ubiquitin Ligase: Discovery and Structure-Activity Relationships of Novel Glutarimide Analogs That Promote Degradation of Aiolos and/or GSPT1
-
We previously disclosed the identification of cereblon modulator 3 (CC-885), with potent antitumor activity mediated through the degradation of GSPT1. We describe herein the structure-activity relationships for analogs of 3 with exploration of the structurally related dioxoisoindoline class. The observed activity of protein degradation could in part be rationalized through docking into the previously disclosed 3-CRBN-GSPT1 cocrystal ternary complex. For SAR that could not be rationalized through the cocrystal complex, we sought to predict SAR through a QSAR model developed in house. Through these analyses, selective protein degradation could be achieved between the two proteins of interest, GSPT1 and Aiolos.
- Hansen, Joshua D.,Condroski, Kevin,Correa, Matthew,Muller, George,Man, Hon-Wah,Ruchelman, Alexander,Zhang, Weihong,Vocanson, Fan,Crea, Tim,Liu, Wei,Lu, Gang,Baculi, Frans,Lebrun, Laurie,Mahmoudi, Afshin,Carmel, Gilles,Hickman, Matt,Lu, Chin-Chun
-
p. 492 - 503
(2018/02/07)
-
- BICYCLIC COMPOUNDS USEFUL AS GPR120 MODULATORS
-
Provided herein are compounds, compositions including them, and methods of modulating GPR120 activity and treating diseases mediated by GPR120 by administering such compounds and compositions.
- -
-
-
- HETEROCYCLIC COMPOUNDS AS INHIBITORS OF RAS AND METHODS OF USE THEREOF
-
Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I): or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein A, B, R", Q, W, X, Y, Z, n1, n2and '--" are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of G12C mutant KRAS protein for treatment of disorders, such as cancer, are also disclosed.
- -
-
Page/Page column 126
(2018/04/21)
-
- Exploring Halogen Bonds in 5-Hydroxytryptamine 2B Receptor-Ligand Interactions
-
Here, we predicted the potential halogen bonding interaction between compound 2 and the 5-hydroxytryptamine 2B (5-HT2B) receptor and systematically assessed this interaction via structure-activity relationship analysis and molecular dynamics simulations. A physics-based computational protocol was then developed to further explore the opportunity of "designing in" halogen bonding interactions in structure-based ligand design for the 5-HT2B receptor, which not only facilitated the identification of previously uncharacterized halogen bonds in known 5-HT2B ligands but also enabled the rational design of halogen bonding interactions for the optimization of 5-HT2B ligands. As a proof-of-concept, a series of halogen-substituted analogues of doxepin was synthesized and evaluated, which showed improved in vitro and in vivo potency.
- Zhou, Yu,Wang, Yuanxun,Li, Pengfei,Huang, Xi-Ping,Qi, Xiangbin,Du, Yunfei,Huang, Niu
-
supporting information
p. 1019 - 1024
(2018/10/15)
-
- COMPOUNDS TARGETING PROTEINS, COMPOSITIONS, METHODS, AND USES THEREOF
-
The present invention provides modulators of protein function, to restore protein homeostasis, including GSPT1 activity. The invention provides methods of modulating protein-mediated diseases, such as GSPT1-mediated diseases, disorders, conditions, or responses. Compositions are also provided. Methods of treatment, amelioration, or prevention of protein-mediated diseases, disorders, and conditions, such as GSPT1-mediated diseases, disorders, and conditions, including cancer and astrogliosis.
- -
-
Paragraph 0267
(2018/10/19)
-
- BENZODIOXANE DERIVATIVES AND THEIR PHARMACEUTICAL USE
-
Compounds of formula (I): wherein Ra and Rb are as defined in the claims, exhibit alpha2C antagonistic activity and are thus useful as alpha2C antagonists.
- -
-
Page/Page column 81
(2018/02/03)
-
- MODULATORS OF ESTROGEN RECEPTOR PROTEOLYSIS AND ASSOCIATED METHODS OF USE
-
The present disclosure relates to bifunctional compounds, which find utility as modulators of estrogen receptor (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a cereblon, Von Hippel-Lindau ligase-binding moiety, Inhibitors of Apotosis Proteins, or mouse double-minute homolog 2 ligand, which binds to the respective E3 ubiquitin ligase, and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.
- -
-
Paragraph 00391
(2018/08/20)
-
- HETEROCYCLIC COMPOUND
-
The present invention provide a heterocyclic compound having a HDAC inhibitory action, and useful for the treatment of autoimmune diseases and/or inflammatory diseases, graft versus host disease, cancers, central nervous diseases including neurodegenerative diseases, Charcot-Marie-Tooth disease and the like, and a pharmaceutical composition comprising the compound. The present invention relates to a compound represented by the formula (I): wherein each symbol is as defined in the specification, or a salt thereof.
- -
-
-
- METHODS FOR TREATING CANCER AND THE USE OF BIOMARKERS AS A PREDICTOR OF CLINICAL SENSITIVITY TO THERAPIES
-
A method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising administering the treatment compound to the subject having the cancer; obtaining a sample from the subject; determining the level of a biomarker in the sample from the subject; and diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample of the subject changes as compared to a reference level of the biomarker; wherein the treatment compound is a compound of Formula I:
- -
-
-
- COMPOSITIONS AND METHODS FOR INDUCING CONFORMATIONAL CHANGES IN CEREBLON AND OTHER E3 UBIQUITIN LIGASES
-
Provided herein are compositions, therapeutic methods, screening methods, computational methods and biomarkers based upon the elucidation of the interaction among cereblon, its substrates and certain compounds or agents, including small molecules, peptides, and proteins.
- -
-
-
- ANTIPROLIFERATIVE COMPOUNDS, AND THEIR PHARMACEUTICAL COMPOSITIONS AND USES
-
Compounds of formula A-I and B-I, compositions comprising the compounds, methods of making the compounds and methods of their uses are disclosed.
- -
-
-
- Bruton tyrosine kinases inhibitor
-
The invention relates to pyrazolo[3,4-d]pyrimidine derivatives, and a preparation method and application thereof to medicines. Concretely, the invention relates to new pyrazolo[3,4-d]pyrimidine derivatives shown as general formulas I and IA, a preparation method of the derivatives, a pharmaceutical composition containing the derivatives, and application of the derivatives as therapy equipment especially as a Bruton tyrosine kinases inhibitor.
- -
-
-
- USE OF BIOMARKERS FOR PREDICTING CLINICAL SENSITIVITY TO CANCER TREATMENT
-
A method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising administering the treatment compound to a subject having cancer; obtaining a sample from the subject; determining the level of a biomarker in the sample from the subject; and diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample of the subject changes as compared to a reference level of the biomarker; wherein the treatment compound is a compound of Formula (I):
- -
-
-
- COMPOUNDS USEFUL AS CSF1 MODULATORS
-
This invention relates to novel compounds and to pharmaceutical compositions comprising the novel compounds. More specifically, the invention relates to compounds useful as Colony Stimulating Factor 1 Receptor (cFMS) modulators (e.g. cFMS inhibitors). This invention also relates to processes for preparing the compounds, uses of the compounds in treatment and methods of treatment employing the compounds. Specifically, the invention relates to the use of the compounds for the treatment of cancer and autoimmune diseases.
- -
-
Paragraph 00527; 00528; 00529
(2016/04/26)
-
- ETHYL N-BOC PIPERIDINYL PYRAZOLO PYRIDONES AS JANUS KINASE INHIBITORS
-
Provided are compounds of Formula I as JAK inhibitors, which are useful for the treatment of JAK-mediated diseases such as rheumatoid arthritis, asthma, COPD and cancer.
- -
-
Page/Page column 61
(2016/05/24)
-
- SUBSTITUTED BENZOFURANYL AND BENZOXAZOLYL COMPOUNDS AND USES THEREOF
-
The invention generally relates to substituted benzofuranyl and substituted benzoxazolyl compounds, and more particularly to a compound represented by Structural Formula (A) : or a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described herein. The invention also includes the synthesis and use of a compound of Structural Formula (A), or a pharmaceutically acceptable salt or composition thereof, e.g., in the treatment of cancer (e.g., mantle cell lymphoma), and other diseases and disorders.
- -
-
-
- Synthesis and biological evaluation of aryl isoxazole derivatives as metabotropic glutamate receptor 1 antagonists: A potential treatment for neuropathic pain
-
Glutamate is the major excitatory neurotransmitter and known to activate the metabotropic and ionotropic glutamate receptors in the brain. Among these glutamate receptors, metabotropic glutamate receptor 1 (mGluR1) has been implicated in various brain disorders including anxiety, schizophrenia and chronic pain. Several studies demonstrated that the blockade of mGluR1 signaling reduced pain responses in animal models, suggesting that mGluR1 is a promising target for the treatment of neuropathic pain. In this study, we have developed mGluR1 antagonists with an aryl isoxazole scaffold, and identify several compounds that are orally active in vivo. We believe that these compounds can serve as a useful tool for the investigation of the role of mGluR1 and a promising lead for the potential treatment of neuropathic pain.
- Cho, Gyeong Hi,Kim, Taehun,Son, Woo Seung,Seo, Seon Hee,Min, Sun-Joon,Cho, Yong Seo,Keum, Gyochang,Jeong, Kyu-Sung,Koh, Hun Yeong,Lee, Jiyoun,Pae, Ae Nim
-
p. 1324 - 1328
(2015/03/14)
-
- NRF2 REGULATORS
-
The present invention relates to bis aryl analogs, pharmaceutical compositions containing them and their use as Nrf2 regulators.
- -
-
-
- COMPOSITIONS AND METHODS FOR INDUCING CONFORMATIONAL CHANGES IN CEREBLON OTHER E3 UBIQUITIN LIGASES
-
Provided herein are compositions, therapeutic methods, screening methods, computational methods and biomarkers based upon the elucidation of the interaction among cerebloR, its substrates and certain compounds or agents, including small molecules, peptides, and proteins.
- -
-
-
- BIOREVERSABLE PROMOIETIES FOR NITROGEN-CONTAINING AND HYDROXYL-CONTAINING DRUGS
-
Disclosed are promoieties of the following formula which can be used to form prodrugs of nitrogen-containing or hydroxyl-containing drug or a pharmaceutically active agent: (I) and pharmaceutical compositions comprising the prodrugs.
- -
-
Page/Page column 136
(2015/06/18)
-
- PERFORIN INHIBITING BENZENESULFONAMIDE COMPOUNDS, PREPARATION AND USES THEREOF
-
Compounds of formula (la) and pharmaceutically acceptable salts, solvates, and hydrates thereof and related methods of modulatin perforin activity on a cell: wherein Ring A is selected from a 6-10 membered aryl, 5-6 membered cycloalkyi, 5-6 membered heteroaryl or 5-6 membered heterocyclyl, wherein the heteroaryl and heterocyclyl rings comprise at least one heteroatom selected from N, O or S; and wherein the aryl, cycloalkyi, heteroaryl or heterocyclyl rings are optionally substituted with 1 to 3 substituents selected from halo, nitro, -C1-Cealkyl, -C1-Ceaminoalkyl, -C1-C6hydroxyalkyl, -haloC1-C6alkyl, -C1- C6alkoxyl, -haloC1-C6alkyl, -CH2OC(O)CrC6alkyl, -C(O)OC1,-C6alkyI, -NHC(O)C1,-C6alkyl, -NHS(O)2C1- C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NH2, and -C(O)NJJ; Ring B is a 6-10 membered arylene or a 5-6 membered heteroarylene comprising at least one heteroatom selected from N, 0 or S; and wherein the aryl or heteroaryl is optionally, substituted with one or more substituents selected from -NJJ, -OJ, halo,C1 -C6alkyl, -haloC1- C6alkyl, -C1-C6alkoxy, -haloC1-C6alkoxyl, and -C(0)NJJ; Ring C is is selected from a 5-10 membered heteroarylene or a 5-10 membered heterocyclene, each comprising at least one heteroatom selected from N, S and O; Ring D is an optionally substituted benzofused 9-11 membered heterocyclyl or optionally substituted ben2ofused 9-11 membered heteroaryl comprising at least one heteroatom selected from N or O; L is a linker selected from branched and unbranched C1-C4 alkylene, -S(0)2-NH-, -C(0)-NH-, -NH-C(0)-NH-, -S(0)2-NH-C(0)-NH-, -S(0)2-NH-C(0) - and -CH=CH-; wherein Rings B and C, and Rings C and D, are connected to each other via a C-C bond at any of the available C atoms on each respective ring; and J in each occurrence is independently selected from H, optionally substituted C1-C6alkyl or optionally substituted haloC1-C6alkyl.
- -
-
-
- Substituted 5,6,11,12-tetradehydrodibenzo[ a, e ]cyclooctenes: Syntheses, properties, and DFT studies of substituted sondheimer-wong diynes
-
Highly strained cyclic acetylenes 5,6,11,12-tetradehydrodibenzo[a,e]cyclooctenes (Sondheimer-Wong diynes) having various substituents on their benzene rings were synthesized successfully by one-pot treatment of the corresponding formyl sulfones with diethyl chlorophosphate/lithium hexamethyldisilazide (LiHMDS) and then lithium diisopropylamide (LDA). When mixtures of two types of formyl sulfones bearing different substituents were subjected to this protocol, the unsymmetrically substituted Sondheimer-Wong diynes could be synthesized in a stepwise manner by isolation of the heterocoupled vinyl sulfone intermediates followed by their treatment with LDA. The UV-vis absorption spectra and cyclic voltammograms of the substituted Sondheimer-Wong diynes were recorded. The electronic effect of substituents on the diynes was investigated in their click reactions and nucleophilic and electrophilic additions.
- Xu, Feng,Peng, Lifen,Shinohara, Kenta,Morita, Takamoto,Yoshida, Suguru,Hosoya, Takamitsu,Orita, Akihiro,Otera, Junzo
-
p. 11592 - 11608
(2015/01/09)
-
- LXR MODULATORS
-
The present invention provides compounds of Formula I and Formula II: or pharmaceutically acceptable salts or solvates thereof, as modulators of liver X receptors (LXRs), and compositions comprising any of such novel compounds and methods of use thereof. These compounds are useful as medicaments for treatment and/or prophylaxis for diseases or conditions related to activity of LXRs.
- -
-
Page/Page column 113; 114
(2014/10/04)
-
- GEMINALLY SUBSTITUTED CYANOETHYLPYRAZOLO PYRIDONES AS JANUS KINASE INHIBITORS
-
The instant invention provides compounds of Formula (I) which are JAK inhibitors, and as such are useful for the treatment of JAK-mediated diseases such as rheumatoid arthritis, asthma, COPD and cancer.
- -
-
Page/Page column 100
(2014/10/03)
-
- Orally active metabotropic glutamate subtype 2 receptor positive allosteric modulators: Structure-activity relationships and assessment in a rat model of nicotine dependence
-
Compounds that modulate metabotropic glutamate subtype 2 (mGlu2) receptors have the potential to treat several disorders of the central nervous system (CNS) including drug dependence. Herein we describe the synthesis and structure-activity relationship (SAR) studies around a series of mGlu 2 receptor positive allosteric modulators (PAMs). The effects of N-substitution (R1) and substitutions on the aryl ring (R 2) were identified as key areas for SAR exploration (Figure 3). Investigation of the effects of varying substituents in both the isoindolinone (2) and benzisothiazolone (3) series led to compounds with improved in vitro potency and/or efficacy. In addition, several analogues exhibited promising pharmacokinetic (PK) properties. Furthermore, compound 2 was shown to dose-dependently decrease nicotine self-administration in rats following oral administration. Our data, showing for the first time efficacy of an mGlu 2 receptor PAM in this in vivo model, suggest potential utility for the treatment of nicotine dependence in humans.
- Sidique, Shyama,Dhanya, Raveendra-Panickar,Sheffler, Douglas J.,Nickols, Hilary Highfield,Yang, Li,Dahl, Russell,Mangravita-Novo, Arianna,Smith, Layton H.,D'Souza, Manoranjan S.,Semenova, Svetlana,Conn, P. Jeffrey,Markou, Athina,Cosford, Nicholas D.P.
-
p. 9434 - 9445
(2013/01/16)
-
- BIARYL PHOSPHODIESTERASE 1NHIBITORS
-
Novel biaryl compounds with phosphodiesterase inhibitory activity of the general formula (I), wherein R1, R2, R3, X, Y, Z1, Z2, Z3, and Z4 have the meanings defined herein, as well as their use as therapeutic agents in the treatment of inflammatory diseases and conditions
- -
-
-
- Bicyclic Derivatives as P38 Inhibitors
-
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.
- -
-
Page/Page column 13
(2010/09/07)
-
- 4, 6-DISUBSTITUTED 2-AMINO-PYRIMIDINES AS HISTAMINE H4 RECEPTOR MODULATORS
-
The present invention relates to substituted heterocyclic compounds of Formula (I) or pharmaceutically acceptable salts or N-oxides or quaternary ammonium salts thereof wherein constituent members are provided hereinwith, as well as their compositions and methods of use, which are histamine H4 receptor inhibitors/antagonists useful in the treatment of histamine H4 receptor-associated conditions or diseases or disorders including, for example, inflammatory diseases or disorders, pruritus, and pain.
- -
-
Page/Page column 184
(2010/07/09)
-
- SYNTHESIS AND USE OF HETEROCYCLIC ANTIBACTERIAL AGENTS
-
This invention relates to compounds of the following Formula (I); or a pharmaceutically acceptable salt, solvate, ester or isomer thereof, which is useful for the treatment of diseases or conditions mediated by LpxC.
- -
-
-
- ISOQUINOLINYL AND ISOINDOLINYL DERIVATIVES AS HISTAMINE-3 ANTAGONISTS
-
The present invention provides a compound of formula I and the use thereof for the treatment of a central nervous system disorder related to or affected by the histamine-3 receptor.
- -
-
Page/Page column 33
(2009/04/24)
-
- AZACYCLYLISOQUINOLINONE AND ISOINDOLINONE DERIVATIVES AS HISTAMINE-3 ANTAGONISTS
-
The present invention provides a compound of formula I and the use thereof for the treatment of a central nervous system disorder related to or affected by the histamine-3 receptor.
- -
-
Page/Page column 18
(2009/04/24)
-
- FUSED PYRAZINE COMPOUNDS USEFUL FOR THE TREATMENT OF DEGENERATIVE AND INFLAMMATORY DISEASES
-
Novel[1.2.4]triazolo[1,5-a]pyrazine and imidazo[1,2-a]pyrazine compounds are disclosed that have a formula represented by the following: The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, pain, inflammation, and others.
- -
-
Page/Page column 28-29
(2009/12/05)
-
- Isoindol-1,3-dione and isoindol-1-one derivatives with high binding affinity to β-amyloid fibrils
-
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
-
p. 1628 - 1631
(2008/09/19)
-
- TRIAZOLOPYRAZINE COMPOUNDS USEFUL FOR THE TREATMENT OF DEGENERATIVE & INFLAMMATORY DISEASES
-
Novel [1.2.4]triazolo[1,5-a]pyrazine compounds are disclosed that have a formula represented by the following (formula I). The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, arthritis, inflammation, and others.
- -
-
-
- BICYCLIC DERIVATIVES AS P38 KINASE INHIBITORS
-
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.
- -
-
Page/Page column 35-36
(2008/06/13)
-
- BICYCLIC DERIVATIVES AS P38 KINASE INHIBITORS
-
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.
- -
-
Page/Page column 30
(2010/11/25)
-
- IMIDAZOLOPYRAZINE COMPOUNDS USEFUL FOR THE TREATMENT OF DEGENERATIVE AND INFLAMMATORY DISEASES
-
Novel imidazo[1,2-a]pyrazine compounds are disclosed that have a formula ( I ) represented by the following:The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, arthritis, inflammation, and others.
- -
-
Page/Page column 90-91
(2008/06/13)
-