- Compound with AMPK agonistic activity and preparation and application of prodrug thereof
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The invention relates to a compound with AMPK agonistic activity and a prodrug thereof, and as well as a preparation method and medical application of a prodrug thereof. The compound has the structure shown in the formula (I), and the prodrug of the compound has the structure shown in the formula (II), wherein each group and the substituent are as defined in the specification. The invention discloses a preparation method of the compound and application of the compound in prevention and treatment AMPK related diseases, and the AMPK related diseases include, but are not limited to, energy metabolism abnormality related diseases. Neurodegenerative diseases and inflammation-related diseases and the like.
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Paragraph 0359-0362
(2021/10/27)
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- Design, synthesis and biological evaluation of novel 2-(4-(1H-indazol-6-yl)-1H-pyrazol-1-yl)acetamide derivatives as potent VEGFR-2 inhibitors
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Vascular endothelial growth factor-2 (VEGFR-2) plays a pivotal role in tumor angiogenesis. Herein, a library of novel 2-(4-(1H-indazol-6-yl)-1H-pyrazol -1-yl)acetamide derivatives were designed and synthesized as VEGFR-2 inhibitors based on scaffold hopping strategy. These compounds exhibited the excellent inhibitory in both VEGFR-2 and tumor cells proliferation. Especially, compound W13 possessed potent VEGFR-2 inhibition with IC50 = 1.6 nM and anti-proliferation against HGC-27 tumor cells with IC50 = 0.36 ± 0.11 μM, as well as less toxicity against normal GES-1 cells with IC50 = 187.46 ± 10.13 μM. Moreover, W13 obviously inhibited colony formation, migration and invasion of HGC-27 cells by adjusting the expression of MMP-9 and E-cadherin, and induced HGC-27 cells apoptosis by increasing ROS production and regulating the expression of apoptotic proteins. Furthermore, W13 blocked the PI3K-Akt-mTOR signaling pathway in HGC-27 cells. In addition, anti-angiogenesis of W13 was proved by inhibiting tube formation and the expression of p-VEGFR-2 in HUVEC cells. All the results demonstrated that W13 could be developing as a promising anticancer agent for gastric cancer therapy.
- Wang, Xing-Rong,Wang, Shuai,Li, Wen-Bo,Xu, Kai-Yan,Qiao, Xue-Peng,Jing, Xue-Li,Wang, Zi-Xiao,Yang, Chang-jiang,Chen, Shi-Wu
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supporting information
(2021/01/26)
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- TYK2 INHIBITORS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of TYK2, and the treatment of TYK2-mediated disorders.
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Paragraph 00453
(2020/06/19)
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- Micromolecular reversible BTK inhibitor for treating rheumatoid arthritis
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The invention relates to a micromolecular reversible BTK inhibitor for treating rheumatoid arthritis, and specifically provides a compound. The compound is the compound as shown in a formula I, or a stereisomer, a geometrical isomer and a tautomer thereof, nitric oxide, aquo-complex, a solvate, a metabolite and pharmaceutically acceptable salts and prodrugs. The inventor finds that polysubstitutedquinolone compound or derivate thereof as shown in formula I can be used as the BTK inhibitor and is high in activity during treating rheumatoid arthritis.
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Paragraph 0140-0144
(2019/07/29)
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- Discovery of 4-Aminoquinoline-3-carboxamide derivatives as potent reversible Bruton's tyrosine kinase inhibitors for the treatment of rheumatoid arthritis
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A structure-hopping strategy was applied to discover a series of novel 4-aminoquinoline-3-carboxamide derivatives as potent, reversible BTK inhibitors. Compared to the previously described cinnoline scaffold compounds, the 4-aminoquinoline analogues showed significantly improved drug-like properties, especially in their aqueous solubility. The most potent compound, 25, displayed a stronger inhibitory effect on both BTKWT (IC50 = 5.3 nM) and BTKC481S (IC50 = 39 nM). In a rodent collagen-induced arthritis model, compound 25 efficiently reduced paw swelling without a loss in body weight. On the basis of potency, drug-like properties, stability, and noncovalent mode of inhibition, our representative inhibitors could have a promising profile to be treatments for a wide range of autoimmune diseases.
- Yao, Xia,Sun, Xiuyun,Jin, Shuyu,Yang, Ling,Xu, Hongjiang,Rao, Yu
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p. 6561 - 6574
(2019/08/20)
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- Discovery of 5-Azaindazole (GNE-955) as a Potent Pan-Pim Inhibitor with Optimized Bioavailability
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Pim kinases have been identified as promising therapeutic targets for hematologic-oncology indications, including multiple myeloma and certain leukemia. Here, we describe our continued efforts in optimizing a lead series by improving bioavailability while maintaining high inhibitory potency against all three Pim kinase isoforms. The discovery of extensive intestinal metabolism and major metabolites helped refine our design strategy, and we observed that optimizing the pharmacokinetic properties first and potency second was a more successful approach than the reverse. In the resulting work, novel analogs such as 20 (GNE-955) were discovered bearing 5-azaindazole core with noncanonical hydrogen bonding to the hinge.
- Wang, Xiaojing,Kolesnikov, Aleksandr,Tay, Suzanne,Chan, Grace,Chao, Qi,Do, Steven,Drummond, Jason,Ebens, Allen J.,Liu, Ning,Ly, Justin,Harstad, Eric,Hu, Huiyong,Moffat, John,Munugalavadla, Veerendra,Murray, Jeremy,Slaga, Dionysos,Tsui, Vickie,Volgraf, Matthew,Wallweber, Heidi,Chang, Jae H.
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p. 4458 - 4473
(2017/06/05)
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- Indazole derivative, composition and uses thereof
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The present invention discloses an indazole derivative represented by a formula (I) and used for treating type 2 diabetes mellitus or a pharmaceutically acceptable salt, a solvate, a metabolite, a polymorph, a tautomer or a prodrug thereof. The present invention further discloses a pharmaceutical composition containing the substance, applications of the composition in preparation of drugs, and a method for treating type II diabetes mellitus. The formula (I) is defined in the specification.
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Paragraph 0117; 0190; 0191
(2017/01/02)
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- A novel series of indazole-/indole-based glucagon receptor antagonists
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A novel, potent series of glucagon receptor antagonists (GRAs) was discovered. These indazole- and indole-based compounds were designed on an earlier pyrazole-based GRA lead MK-0893. Structure-activity relationship (SAR) studies were focused on the C3 and C6 positions of the indazole core, as well as the benzylic position on the N-1 of indazole. Multiple potent GRAs were identified with excellent in vitro profiles and good pharmacokinetics in rat. Among them, GRA 16d was found to be orally active in blunting glucagon induced glucose excursion in an acute glucagon challenge model in glucagon receptor humanized (hGCGR) mice at 1, 3 and 10 mg/kg (mpk), and significantly lowered acute glucose levels in hGCGR ob/ob mice at 3 mpk dose.
- Lin, Songnian,Zhang, Fengqi,Jiang, Guoqiang,Qureshi, Sajjad A.,Yang, Xiaodong,Chicchi, Gary G.,Tota, Laurie,Bansal, Alka,Brady, Edward,Trujillo, Maria,Salituro, Gino,Miller, Corey,Tata, James R.,Zhang, Bei B.,Parmee, Emma R.
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p. 4143 - 4147
(2015/11/03)
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- AZA SPIRO ALKANE DERIVATIVES AS INHIBITORS OF METALLPROTEASES
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The present invention provides a compound of Formula (I) or Formula (II): enantiomer, diastereomer, prodrug, solvate, metabolite, or pharmaceutically acceptable salt thereof, wherein constituent variables are provided herein. The compounds of Formula (I) and (II) are modulators of metalloproteases and are useful in treating diseases associated with metalloprotease activity such as arthritis, cancer, cardiovascular disorders, skin disorders, inflammation and allergic conditions.
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Paragraph 0410
(2015/12/18)
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- INHIBITORS OF FATTY ACID AMIDE HYDROLASE
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The present invention provides compounds, and pharmaceutically acceptable compositions thereof, encompassed by any of formulae (I), (II), (III), (IV), (V), or (VI), or subgenera thereof. The present invention also provides methods for treating an FAAH mediated disease, disorder or condition by administering a therapeutically effective amount of a compound or composition comprising a compound of any of formulae (I), (II), (III), (IV), (V), or (VI), or subgenera thereof, to a patient in need thereof. Additionally, the present invention provides methods for inhibiting FAAH by administering a therapeutically effective amount of a compound or composition comprising a compound of any of formulae (I), (II), (III), (IV), (V), or (VI), or subgenera thereof, to a patient in need thereof.
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Paragraph 1273; 1274
(2016/01/15)
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- A general, one-step synthesis of substituted indazoles using a flow reactor
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Flow chemistry is a rapidly emerging technology within the pharmaceutical industry, both within medicinal and development chemistry groups. The advantages of flow chemistry, increased safety, improved reproducibility, enhanced scalability, are readily apparent, and we aimed to exploit this technology in order to provide small amounts of pharmaceutically interesting fragments via a safe and scalable route, which would enable the rapid synthesis of multigram quantities on demand. Here we report a general and versatile route which utilises flow chemistry to deliver a range of known and novel indazoles, including 3-amino and 3-hydroxy analogues.
- Wheeler, Rob C.,Baxter, Emma,Campbell, Ian B.,MacDonald, Simon J. F.
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experimental part
p. 565 - 569
(2011/12/02)
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- INDAZOLYL, BENZIMIDAZOLYL, BENZOTRIAZOLYL SUBSTITUTED INDOLMONE DERIVATIVES AS KINASE INHIBITORS USEFUL IN THE TREATMENT OF CANCER
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The present invention is directed to a compound is represented by Structural Formula (A):or a pharmaceutically acceptable salt therof. The present invention is also directed to a pharmaceutical composition comprising a compound represented by Structural Formula (A) described above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. Also disclosed is a method of treating a subject having cancer, wherein the method comprises administering a therapeutically effective amount of a compound represented by Structural Formula (A) described above or a pharmaceutically acceptable salt thereof.
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Page/Page column 84
(2009/07/25)
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- 6' SUBSTITUTED COMPOUNDS HAVING 5-HT6 RECEPTOR AFFINITY
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The present disclosure provides compounds having affinity for the 5-HT6 receptor which are of the formula (I): wherein R1—R4 A, B, D, E, and G are as defined herein. The disclosure also relates to methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.
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Page/Page column 34; 35
(2008/12/08)
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- Thiazole compounds and methods of use
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The invention relates to thiazole compounds of Formula I and Formula II and compositions thereof useful for treating diseases mediated by protein kinase B (PKB) where the variables have the definitions provided herein. The invention also relates to the therapeutic use of such thiazole compounds and compositions thereof in treating disease states associated with abnormal cell growth, cancer, inflammation, and metabolic disorders.
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Page/Page column 48
(2008/06/13)
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- 4-Substituted indazoles as new inhibitors of neuronal nitric oxide synthase
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A series of halo-1-H-indazoles has been synthesized and evaluated for its inhibitory activity on neuronal nitric oxide synthase. Introduction of bromine at the C4 position of the indazole ring system provided a compound almost as potent as the reference compound, that is, 7-nitroindazole (7-NI). The importance of position 4 is further demonstrated by the synthesis and pharmacological evaluation of the 4-nitroindazole which was also a potent inhibitor of NOS activity. These compounds also exhibited in vivo NOS inhibitory activity, as attested by potent antinociceptive effects following systemic administration.
- Boulouard, Michel,Schumann-Bard, Pascale,Butt-Gueulle, Sabrina,Lohou, Elodie,Stiebing, Silvia,Collot, Valerie,Rault, Sylvain
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p. 3177 - 3180
(2008/02/04)
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- Aminopyrazine analogs for treating glaucoma and other rho kinase-mediated diseases and conditions
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Methods for using aminopyrazine analogs to treat rho kinase-mediated diseases or rho kinase-mediated conditions, including controlling intraocular pressure and treating glaucoma, are disclosed. Ophthalmic pharmaceutical compositions useful in the treatment of eye diseases such as glaucoma, and additionally useful for controlling intraocular pressure, the compositions comprising an effective amount of aminopyrazine analogs, are also disclosed.
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Page/Page column 8
(2008/06/13)
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- New practical synthesis of indazoles via condensation of o-fluorobenzaldehydes and their O-methyloximes with hydrazine
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The reaction of o-fluorobenzaldehydes and their O-methyloximes with hydrazine has been developed as a new practical synthesis of indazoles. Utilization of the methyloxime derivatives of benzaldehydes (in the form of the major E-isomers) in this condensation effectively eliminated a competitive Wolf-Kishner reduction to fluorotoluenes, which was observed in the direct preparations of indazoles from aldehydes. Reaction of Z-isomers of methyloximes with hydrazine resulted in the formation of 3-aminoindazoles via a benzonitrile intermediate.
- Lukin, Kirill,Hsu, Margaret C.,Fernando, Dilinie,Leanna, M. Robert
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p. 8166 - 8172
(2007/10/03)
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- 3-(Indol-2-yl)indazoles as Chek1 kinase inhibitors: Optimization of potency and selectivity via substitution at C6
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The development of 3-(indol-2-yl)indazoles as inhibitors of Chek1 kinase is described. Introduction of amides and heteroaryl groups at the C6 position of the indazole ring system provided sufficient Chek1 potency and selectivity over Cdk7 to permit escape from DNA damage-induced arrest in a cellular assay. Enzyme potency against Chek1 was optimized by the incorporation of a hydroxymethyl triazole moiety in compound 21 (Chek1 IC50 = 0.30 nM) that was shown by X-ray crystallography to displace one of three highly conserved water molecules in the HI region of the ATP-binding cleft.
- Fraley, Mark E.,Steen, Justin T.,Brnardic, Edward J.,Arrington, Kenneth L.,Spencer, Keith L.,Hanney, Barbara A.,Kim, Yuntae,Hartman, George D.,Stirdivant, Steven M.,Drakas, Bob A.,Rickert, Keith,Walsh, Eileen S.,Hamilton, Kelly,Buser, Carolyn A.,Hardwick, James,Tao, Weikang,Beck, Stephen C.,Mao, Xianzhi,Lobell, Robert B.,Sepp-Lorenzino, Laura,Yan, Youwei,Ikuta, Mari,Munshi, Sanjeev K.,Kuo, Lawrence C.,Kreatsoulas, Constantine
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p. 6049 - 6053
(2007/10/03)
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- INDAZOLES, BENZOTHIAZOLES, AND BENZOISOTHIAZOLES, AND PREPARATION AND USES THEREOF
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The present invention relates generally to the field of ligands for nicotinic acetylcholine receptors (nAChR), activation of nAChRs, and the treatment of disease conditions associated with defective or malfunctioning nicotinic acetylcholine receptors, especially of the brain. Further, this invention relates to novel compounds (indazoles and benzothiazoles), which act as ligands for the α7 nAChR subtype, methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.
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- Substituted phenylalkanoic acid derivatives and use thereof
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A compound represented by the formula (I) or a salt thereof: wherein n represents an integer of 1 to 3, R represents an alkyl group having 3 to 8 carbon atoms, a group represented by the following formula: R1(CH2)k— (wherein k represents 0 or an integer of 1 to 3; R1 represents a saturated cyclic alkyl group having 3 to 7 carbon atoms or a saturated condensed cyclic alkyl group having 6 to 8 carbon atoms, and the group R1 may be substituted with a lower alkyl group having 1 to 4 carbon atoms) and the like, and Ar represents a condensed bicyclic group such as naphthalen-1-yl group, which has suppressing action on prostaglandin and leukotriene production and is useful for prophylactic and/or therapeutic treatment of various inflammatory diseases and the like caused by these lipid mediators.
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- N-alkylamino-indoles for the treatment of migraine
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The present invention is directed to compounds useful in the treatment of migraine which have the general formula (II).
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