- Novel indirect AMP-activated protein kinase activators: Identification of a second-generation clinical candidate with improved physicochemical properties and reduced hERG inhibitory activity
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This study reports the synthesis and evaluation of novel indirect AMP-activated protein kinase (AMPK) activators. The series of compounds selectively inhibited cell growth in several human breast cancer cell lines by activating AMPK. We performed back-up medicinal chemistry synthetic research on ASP4132, a previously reported as a compound for clinical development that acts as an indirect AMPK activator. This led to the successful identification of 4-({4-[5-({1-[(5-ethoxypyrazin-2-yl)methyl]-4-fluoropiperidin-4-yl}methoxy)-3-methylpyridine-2-carbonyl]piperazin-1-yl}methyl)benzonitrile succinate (27b), a potent, highly aqueous soluble and metabolically stable compound in human hepatocytes. Compound 27b also showed weaker human Ether-a-go-go Related Gene (hERG) inhibitory activity than that of compound 13 and ASP4132. Therefore, 27b was a promising AMPK activator and a second-generation clinical candidate for treatment for human cancer.
- Kuramoto, Kazuyuki,Sawada, Yuki,Yamada, Tomohiro,Nagashima, Takeyuki,Ohnuki, Kei,Shin, Takashi
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p. 452 - 465
(2020/09/09)
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- HETEROCYCLIC COMPOUNDS AND THEIR USE FOR TREATMENT OF HELMINTHIC INFECTIONS AND DISEASES
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Provided herein are Heterocyclic compounds of formula (I): and pharmaceutically acceptable salts, tautomers, isotopologues, or stereoisomers thereof, wherein W, X, Y, R1, R2, and RN are as defined herein, compositions comprising an effective amount of a Heterocyclic Compound, and methods for treating or preventing animal and human filarial worm infections and diseases.
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Paragraph 00314
(2020/11/03)
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- As neuroprotective agents of pharmaceutical compounds
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The invention discloses a medicinal compound as a neuroprotective agent. The medicinal compound is a neuronal nitric oxide synthase-postsynaptic density protein 95 (nNOS-PSD95) decoupling agent. The medicinal compound is a benzene ring derivative shown in the general formula (I) or its pharmaceutically acceptable salt. The invention further discloses a preparation method of the medicinal compound and a use of the medicinal compound in prevention and treatment on neuronal damage influence-caused diseases.
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Paragraph 0314; 0315; 0316; 0317
(2019/06/26)
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- MODIFIED COMPOUND OF ANDROGRAPHOLIDE
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The present disclosure discloses a modified compound of andrographolide, and particularly discloses a compound shown in formula (I) and (II) or a pharmaceutically acceptable salt thereof.
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Paragraph 0260-0262
(2019/01/04)
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- PYRIDINEAMINE COMPOUNDS USEFUL AS PIM KINASE INHIBITORS
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The present disclosure describes pyridineamine compounds, as well as their compositions and methods of use. The compounds inhibit the activity of the Pim kinases, and are useful in the treatment of diseases related to the activity of Pim kinases including, e.g., cancer, immune disorders and other diseases. Formula (I).
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Page/Page column 71-72
(2016/12/22)
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- QUINOLINE AND QUINAZOLINE COMPOUNDS
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In some embodiments, the invention relates to quinazoline and quinoline compounds of Formula I: (I) or a pharmaceutically acceptable salt thereof, or to pharmaceutical compositions comprising these compounds and to their use in therapy. In particular, in some embodiments, the present invention relates to quinazoline and quinoline compounds, pharmaceutical compositions thereof, and the use of the compounds and pharmaceutical compositions in the treatment of Bruton's tyrosine kinase (BTK) mediated disorders.
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Paragraph 00306
(2016/05/02)
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- BICYCLIC HETEROAROMATIC CARBOXAMIDE COMPOUNDS USEFUL AS PIM KINASE INHIBITORS
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The present disclosure describes bicyclic heteroaromatic carboxamide derivatives of formula (I), as well as their compositions and methods of use. The compounds inhibit the activity of the Pim kinases, and are useful in the treatment of diseases related to the activity of Pim kinases including, e.g., cancer and other diseases.
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Page/Page column 96-97
(2016/02/26)
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- THIAZALOPYRROLIDINE INHIBITORS OF ROR-GAMMA
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Provided are novel compounds of Formula (I): pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which are useful in the treatment of diseases and disorders mediated by ROR?. Also provided are pharmaceutical compositions comprising the novel compounds of Formula (I) and methods for their use in treating one or more inflammatory, metabolic, autoimmune and other diseases or disorders.
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Paragraph 00198
(2014/11/13)
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- COMPOUNDS AND METHODS
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The present invention relates to novel retinoid-reiated orphan receptor gamma (RORy) modulators and their use in the treatment of diseases mediated by RORy.
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Page/Page column 62
(2013/03/26)
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- THERAPEUTIC METHODS
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The present invention relates to methods of treatment of diseases mediated by ROR?.
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Page/Page column 52
(2013/06/27)
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- TRIAZOLE DERIVATIVES AS WNT SIGNALING PATHWAY INHIBITORS
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The present invention relates to compounds of formula (I), to processes for their preparation, to pharmaceutical formulations containing such compounds and to their use in therapy: Such compounds find particular use in the treatment and/or prevention of conditions or diseases which are affected by over-activation of signaling in the Wnt pathway and increased presence of nuclear β-catenin. For example, these may be used in preventing and/or retarding proliferation of tumor cells and metastasis, for example carcinomas such as colon carcinomas.
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Page/Page column 82
(2012/06/30)
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- Novel tetrahydropyrido[1,2-a]isoindolone derivatives (valmerins): Potent cyclin-dependent kinase/glycogen synthase kinase 3 inhibitors with antiproliferative activities and antitumor effects in human tumor xenografts
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The development of CDK and GSK3 inhibitors has been regarded as a potential therapeutic approach, and a substantial number of diverse structures have been reported to inhibit CDKs and GSK-3β in recent years. Only a few molecules have gone through or are currently undergoing clinical trials as CDK and GSK inhibitors. In this paper, we prepared valmerins, a new family containing the tetrahydropyrido[1,2-a]isoindone core. The fused heterocycle was prepared with a straightforward synthesis that was functionalized by a (het)arylurea. Twelve valmerins inhibited the CDK5 and GSK3 with an IC50 100 nM. A semiquantitative kinase scoring was realized, and a cellular screening was done. At the end of our study, we investigated the in vivo potency of one valmerin. Mice exhibited good tolerance to our lead, which proved its efficacy and clearly blocked tumor growth. Valmerins appear also as good candidates for further development as anticancer agents.
- Boulahjar, Rajaa,Ouach, Aziz,Matteo, Chiurato,Bourg, Stephane,Ravache, Myriam,Guével, Rémy Le,Marionneau, Séverine,Oullier, Thibauld,Lozach, Olivier,Meijer, Laurent,Guguen-Guillouzo, Christiane,Lazar, Sa?d,Akssira, Mohamed,Troin, Yves,Guillaumet, Gérald,Routier, Sylvain
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p. 9589 - 9606
(2013/01/16)
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- Thieno-pyrimidine compounds having fungicidal activity
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The present invention relates to thieno[2,3-d]-pyrimidine compounds having fungicidal activity.
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Page/Page column 33-34
(2010/11/08)
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- 2-Pyridinecarboxylic acids
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5-Etherified 2-pyridinecarboxylic acids, e.g. those of the formula STR1 or functional derivatives thereof, are hypotensive agents.
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- 2-Pyridinecarbonitrile compounds
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5-Etherified 2-pyridinecarboxylic acids, e.g. those of the formula STR1 R = phenyl or (alkyl, alkoxy, halogeno, CF3, CN, CONH2 or NH2)-phenyl R' = H or carboxy X = O or S, m = 1-4 or functional derivative thereof, are hypotensive agents.
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- Selectively herbicidal 4,6-dibromo-5-hydroxy-2-pyridine carboxamide, salts and esters thereof and methods of preparation and use
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The invention is a genus of compounds of the formula STR1 wherein X is --OH, --OM, --OR or --NH2 ; Y is H, M or R'C0--; R is a primary or secondary C1 --C12 alkyl group, a C5 --C7 cycloalkyl group, phenyl or a C7 --C12 phenalkyl or alylphenyl group; R' is a C1 --C11 alkyl or alkenyl group, a C5 --C7 cycloalkyl or cycloalkenyl group, phenyl or a C7 --C12 phenyl alkyl, phenylalkenyl, alkylphenyl or alkenylphenyl group and M, independently, is a metal or ammonium cation. The compounds in which X is --NH2 are uniquely selective post-emergent herbicides for control of both broadleaf weeds and wild oats in grains such as wheat and barley. The compounds in which X is not NH2 have utility as intermediates and some of them are biologically active.
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