- 1-[2-(1-Cyclobutylpiperidin-4-yloxy)-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl]propan-1-one: a Histamine H3 Receptor Inverse Agonist with Efficacy in Animal Models of Cognition
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A series of chemical optimizations, which was guided by in vitro affinity at histamine H3 receptor (H3R), modulation of lipophilicity, ADME properties and preclinical efficacy resulted in the identification of 1-[2-(1-cyclobutylpiperidin-4-yloxy)-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl]propan-1-one (45 e) as a potent and selective (Ki=4.0 nM) H3R inverse agonist. Dipsogenia induced by (R)-α-methylhistamine was dose dependently antagonized by 45 e, confirming its functional antagonism at H3R. It is devoid of hERG and phospholipidosis issues. Compound 45 e has adequate oral exposures and favorable half-life in both rats and dogs. It has demonstrated high receptor occupancy (ED80=0.22 mg/kg) and robust efficacy in object recognition task and, dose dependently increased acetylcholine levels in brain. The sub-therapeutic doses of 45 e in combination with donepezil significantly increased acetylcholine levels. The potent affinity, selectivity, in vivo efficacy and drug like properties together with safety, warrant for further development of this molecule for potential treatment of cognitive disorders associated with Alzheimer's disease.
- Shinde, Anil Karbhari,Badange, Rajesh Kumar,Reballi, Veena,Achanta, Pramod Kumar,Bojja, Kumar,Manchineella, Sravanthi,Rao Muddana, Nageswara,Subramanian, Ramkumar,Choudary Palacharla, Raghava,Benade, Vijay,Jayarajan, Pradeep,Thentu, Jagadeesh Babu,Lingavarapu, Bujji Babu,Yarra, Sivasekhar,Kagita, Narendra,Rao Doguparthi, Mallikarjuna,Mohammed, Abdul Rasheed,Nirogi, Ramakrishna
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- FLUOROALLYLAMINE DERIVATIVE AND USE THEREOF
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The present invention relates to a fluoroallylamine derivative and use thereof. In particular, the present invention relates to a compound as shown in Formula I, a prodrug, an isomer, an isotope-labeled compound, a solvate or a pharmaceutically acceptable salt thereof, which has VAP-1/SSAO inhibitory activity, and can be used for treating a disease associated with VAP-1/SSAO overactivity.
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Paragraph 0265
(2020/03/17)
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- Discovery of 5-phenoxy-2-aminopyridine derivatives as potent and selective irreversible inhibitors of bruton’s tyrosine kinase
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As a member of the tyrosine protein kinase Tec (TEC) family, Bruton’s tyrosine kinase (BTK) is considered a promising therapeutic target due to its crucial roles in the B cell receptor (BCR) signaling pathway. Although many types of BTK inhibitors have been reported, there is an unmet need to achieve selective BTK inhibitors to reduce side effects. To obtain BTK selectivity and efficacy, we designed a novel series of type II BTK inhibitors which can occupy the allosteric pocket induced by the DFG-out conformation and introduced an electrophilic warhead for targeting Cys481. In this article, we have described the structure-activity relationships (SARs) leading to a novel series of potent and selective piperazine and tetrahydroisoquinoline linked 5-phenoxy-2-aminopyridine irreversible inhibitors of BTK. Compound 18g showed good potency and selectivity, and its biological activity was evaluated in hematological tumor cell lines. The in vivo efficacy of 18g was also tested in a Raji xenograft mouse model, and it significantly reduced tumor size, with 46.8% inhibition compared with vehicle. Therefore, we have presented the novel, potent, and selective irreversible inhibitor 18g as a type II BTK inhibitor.
- Cho, Hyewon,Choi, Byeong Jo,Ha, Ju Hyun,Jeon, Raok,Jeong, Ji Hye,Kang, Jong Soon,Lee, Da Kyung,Lee, Eun,Ryu, Jae-Ha
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- Quinoline and Isoquinoline Based HDAC Inhibitors and Methods of Use Thereof
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The present invention relates to methods of modulating activity of histone deacetylases (HDACs). The present invention also relates to methods of treating HDAC-associated diseases including, but not limited to, cancers, inflammatory disorders, and neurode
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- Halogenated allyl amine type SSAO/VAP-1 inhibitor and application thereof
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The invention belongs to the technical field of medicine, and particularly relates to a halogenated allyl amine type compound shown as a formula I, medically acceptable salt, ester or stereo isomers thereof, wherein R1, R2, R3, R4, R5, R6, L1, Cy1, R7 and p are defined in description. The invention also relates to a medicine preparation containing the compounds, a medicine composition containing the compounds, and application of the compounds to prevention and/or treatment on diseases relevant to SSAO/VAP 1 protein or diseases caused by SSAO/VAP 1 protein mediating. The formula I is shown in the description.
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Paragraph 0242; 0246-0248; 0252; 0256-0258
(2019/06/08)
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- Light-Driven Intramolecular C?N Cross-Coupling via a Long-Lived Photoactive Photoisomer Complex
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Reported herein is a visible-light-driven intramolecular C?N cross-coupling reaction under mild reaction conditions (metal- and photocatalyst-free, at room temperature) via a long-lived photoactive photoisomer complex. This strategy was used to rapidly prepare the N-substituted polycyclic quinazolinone derivatives with a broad substrate scope (>50 examples) and further exploited to synthesize the natural products tryptanthrin, rutaecarpine, and their analogues. The success of gram-scale synthesis and solar-driven transformation, as well as promising tumor-suppressing biological activity, proves the potential of this strategy for practical applications. Mechanistic investigations, including control experiments, DFT calculations, UV-vis spectroscopy, EPR, and X-ray single-crystal structure of the key intermediate, provides insight into the mechanism.
- Jing, Dong,Lu, Cong,Chen, Zhuo,Jin, Songyang,Xie, Lijuan,Meng, Ziyi,Su, Zhishan,Zheng, Ke
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p. 14666 - 14672
(2019/09/06)
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- Quantum Dot Based Luminescent Nanoprobes for Sigma-2 Receptor Imaging
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The increasing importance of sigma-2 receptor as target for the diagnosis and therapy of tumors paves the way for the development of innovative optically traceable fluorescent probes as tumor cell contrast and therapeutic agents. Here, a novel hybrid organic-inorganic nanostructure is developed by combining the superior fluorescent properties of inorganic quantum dots (QDs), coated with a hydrophilic silica shell (QD@SiO2 NPs), the versatility of the silica shell, and the high selectivity for sigma-2 receptor of the two synthetic ligands, namely, the 6-[(6-aminohexyl)oxy]-2-(3-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)propyl)-3,4-dihydroisoquinolin-1(2H)-one (MLP66) and 6-[1-[3-(4-cyclohexylpiperazin-1-yl)propyl]-1,2,3,4-tetrahydronaphthalen-5-yloxy]hexylamine (TA6). The proposed nanostructures represent a challenging alternative to all previously studied organic small fluorescent molecules, based on the same sigma-2 receptor affinity moieties. Flow cytometry and confocal fluorescence microscopy experiments, respectively, on fixed and living cancerous MCF7 cells, which overexpress the sigma-2 receptor, prove the ability of functionalized (QD@SiO2-TA6 and QD@SiO2-MLP66) NPs to be internalized and demonstrate their affinity to the sigma-2 receptor, ultimately validating the targeting properties conveyed to the NPs by sigma-2 ligand conjugation. The presented QD-based nanoprobes possess a great potential as in vitro selective sigma-2 receptor imaging agent and, consequently, could provide a significant impact to future theranostic applications.
- Pati, Maria Laura,Fanizza, Elisabetta,Hager, Sonja,Groza, Diana,Heffeter, Petra,Laurenza, Amelita Grazia,Laquintana, Valentino,Curri, Maria Lucia,Depalo, Nicoletta,Abate, Carmen,Denora, Nunzio
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p. 458 - 471
(2018/02/14)
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- 1,2,3,4-TETRAHYDROISOQUINOLINE COMPOUNDS AND COMPOSITIONS AS SELECTIVE ESTROGEN RECEPTOR ANTAGONISTS AND DEGRADERS
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The present invention relates to compounds of formula (I) in which n, R1, R2, R3, R4and R5 are as defined in the claims; capable of being both potent antagonists and degraders of estrogen receptors. Also described is a process for the preparation of compounds of the invention, and the invention further provides pharmaceutical preparations comprising such compounds and methods of using such compounds and compositions in the management of diseases or disorders associated with aberrant estrogen receptor activity.
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Paragraph 00327
(2015/07/07)
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- 2-(Pyrrolidin-1-yl)ethyl-3,4-dihydroisoquinolin-1(2H)-one derivatives as potent and selective histamine-3 receptor antagonists
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On the basis of the previously reported benzimidazole 1,3′- bipyrrolidine benzamides (1), a new class of 2-(pyrrolidin-1-yl)ethyl-3,4- dihydroisoquinolin-1(2H)-one derivatives (3-50) were synthesized and evaluated as potent H3 receptor antagonists. In particular, compound 39 exhibited potent in vitro binding and functional activities at the H3 receptor, good selectivities against other neurotransmitter receptors and ion channels, acceptable pharmacokinetic properties, and a favorable in vivo profile.
- Zhou, Dahui,Gross, Jonathan L.,Adedoyin, Adedayo B.,Aschmies, Suzan B.,Brennan, Julie,Bowlby, Mark,Di, Li,Kubek, Katie,Platt, Brian J.,Wang, Zheng,Zhang, Guoming,Brandon, Nicholas,Comery, Thomas A.,Robichaud, Albert J.
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p. 2452 - 2468
(2012/05/05)
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- Design, synthesis, and structure-activity relationship studies of conformationally restricted mutilin 14-carbamates
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We report herein the design, synthesis, and structure-activity relationship studies of conformationally restricted mutilin 14-carbamates based on the structure of SB-222734. The antibacterial activities of these newly synthesized compounds were also evaluated and compared with linezolid and retapamulin. Results showed that most of the target compounds exhibit good potency in inhibiting the growth of Gram-positive bacteria including Methicillin- susceptible Staphylococcus aureus MSSA (MIC: 0.0625-2 μg/mL), Methicillin-resistant S. aureus MRSA (MIC: 0.0625-2 μg/mL), Methicillin-susceptible Staphylococcus epidermidis MSSE (MIC: 0.0625-2 μg/mL), Methicillin-resistant S. epidermidis MRSE (MIC: 0.0625-2 μg/mL), and Streptococcus pneumonia (MIC: 0.0625-4 μg/mL). In particular, three remarkable compounds of this series (12l, 12m, and 21l) exhibited comparable in vitro antibacterial profiles to that of retapamulin.
- Fu, Liqiang,Liu, Xin,Ling, Chenyu,Cheng, Jianjun,Guo, Xingsheng,He, Huili,Ding, Shi,Yang, Yushe
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p. 814 - 819
(2012/03/11)
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- ISOQUINOLINYL AND ISOINDOLINYL DERIVATIVES AS HISTAMINE-3 ANTAGONISTS
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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.
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Page/Page column 23
(2009/04/24)
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- 3-(4-(6-Fluoroalkoxy-3,4-dihydroisoquinoline-2(1H)-yl)cyclohexyl)-1H-indole-5-carbonitriles for SERT imaging: Chemical synthesis, evaluation in vitro and radiofluorination
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Aminocyclohexyl indoles bind with high affinity and specificity toward the serotonin transporter (SERT). Based on this structural lead, we designed fluoroalkoxydihydroisoquinoline-cyclohexyl indole carbonitriles for future application as 18F-labeled tracers for SERT imaging by PET. Six compounds, three pairs of cis- and trans-isomer derivatives, respectively, were synthesized and evaluated in vitro. The chemistry of the new compounds, their affinity and specificity data, the general route to the phenolic precursor for labeling, and the successful 18F-fluoroalkylation of one pair of compounds are described herein.
- Funke, Uta,Fischer, Steffen,Hiller, Achim,Scheunemann, Matthias,Deuther-Conrad, Winnie,Brust, Peter,Steinbach, Joerg
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scheme or table
p. 4727 - 4730
(2009/04/08)
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- NITROGEN HETEROCYCLE BIARYLS FOR OSTEOPOROSIS AND OTHER DISEASES
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Nitrogen heterocycle biaryls having a carboxylate terminus are useful for treating endometriosis, osteoporosis, restenosis following angioplasty, rheumatoid arthritis, cancer, macular degeneration and obesity. Compounds of formula: (I) are disclosed. A re
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Page/Page column 52-53
(2010/11/25)
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- COMPOUNDS AND COMPOSITIONS AS PPAR MODULATORS
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The invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with the activity of the Peroxisome Proliferator-Activated Receptor (PPAR) families.
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Page/Page column 23
(2008/06/13)
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- ENZYME MODULATORS AND TREATMENTS
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Novel compounds and methods of using those compounds for the treatment of inflammatory conditions, hyperproliferative diseases, cancer, and diseases characterized by hypervascularization are provided. In a preferred embodiment, modulation of the activation state of p38 kinase protein ab1 kinase protein, bcr-ab1 kinase protein, braf kinase protein, VEGFR kinase protein, or PDGFR kinase protein comprises the step of contacting said kinase protein with the novel compounds.
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Page/Page column 420
(2008/06/13)
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- Nitrogen heterocycle biaryls for osteoporosis and other diseases
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Nitrogen heterocycle biaryls having a carboxylate terminus are useful for treating endometriosis, osteoporosis, restenosis following angioplasty, rheumatoid arthritis, cancer, macular degeneration and obesity. Compounds of formula: are disclosed. A representative example is
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Page/Page column 19-20
(2010/02/14)
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- Isoquinoline derivatives
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Disclosed are isoquinolino derivatives of the formula wherein Y is >C═O or —CH2—, Z is >C═O or —CH2—, and R1, R2 and m are as defined herein as well as the pharmaceutically acceptable salts thereof. These compounds are MAO-B selective inhibitors useful, inter alia, in the treatment of Alzheimer's disease and/or senile dementia.
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- Lactam derivatives as antiarrhythmic agents
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Lactam derivatives of the formula where X is —C(═O)NR3′—, —NR3′C(═O)—, —C(═NCN)NR3′—, —NR3′C(═NCN)—, —CH2NR3′—, —CH(alkyl)NR3′—, —CH(COOalkyl)NR3′—, —CH(CH2
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- 2,3-diaminopropionic acid derivative
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The present invention relates to a 2,3-diaminopropionic acid derivative of the formula (1): STR1 or a pharmaceutically acceptable salt thereof. The compounds of the present invention are useful as a platelet aggregation inhibitor, a cancer metastasis inhibitor, a wound healing agent or a bone resorption inhibitor.
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- Isoquinolyl substituted hydroxylamine derivatives
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The compounds of the formula STR1 wherein R represents hydrogen, lower alkyl, aryl, biaryl, C3 -C7 -cycloalkyl, aryl-lower alkyl, aryl-lower alkenyl, aryl-lower alkynyl, aryloxy-lower alkyl, arylthio-lower alkyl, C3 -Csub
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- ISOQUINOLYL SUBSTITUTED HYDROXYLAMINE DERIVATIVES
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The compounds of the formula wherein R represents hydrogen, lower alkyl, aryl, biaryl, C3-C7-cycloalkyl, aryl-lower alkyl, aryl-lower alkenyl, aryl-lower alkynyl, aryloxy-lower alkyl, arylthio-lower alkyl; C3-C7-cycloalkyl-lower alkyl, biaryl-lower alkyl,
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