- Discovery of indazole-pyridinone derivatives as a novel class of potent and selective MNK1/2 kinase inhibitors that protecting against endotoxin-induced septic shock
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The mitogen-activated protein kinase (MAPK)-interacting kinases 1 and 2 (MNKs 1/2) and their downstream target eIF4E, play a role in oncogenic transformation, progression and metastasis. These results provided rationale for development of first MNKs inhibitors, currently in clinical trials for cancer treatment. Inhibitors of the MNKs/eIF4E pathway are also proposed as treatment strategy for inflammatory conditions. Here we present results of optimization of indazole-pyridinone derived MNK1/2 inhibitors among which compounds 24 and 26, selective and metabolically stable derivatives. Both compounds decreased levels of eIF4E Ser206 phosphorylation (pSer209-eIF4E) in MOLM16 cell line. When administered in mice compounds 24 and 26 significantly improved survival rates of animals in the endotoxin lethal dose challenge model, with concomitant reduction of proinflammatory cytokine levels – TNFα and IL-6 in serum. Identified MNK1/2 inhibitors represent a novel class of immunomodulatory compounds with a potential for the treatment of inflammatory diseases including sepsis.
- Dreas, Agnieszka,Kucwaj-Brysz, Katarzyna,Pyziak, Karolina,Kulesza, Urszula,Wincza, Ewelina,Fabritius, Charles-Henry,Michalik, Kinga,Gabor-Worwa, Ewelina,Go?as, Aniela,Milik, Mariusz,Masiejczyk, Magdalena,Majewska, Eliza,Py?niak, Kazimiera,Wójcik-Trechcińska, Urszula,Sandowska-Markiewicz, Zuzanna,Brzózka, Krzysztof,Ostrowski, Jerzy,Rzymski, Tomasz,Mikula, Michal
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supporting information
(2020/12/13)
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- PYRIDINONE DERIVATIVES AND THEIR USE AS SELECTIVE ALK-2 INHIBITORS
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The invention relates to a compound of Formula I or a pharmaceutically acceptable salt thereof, a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.
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Page/Page column 48-49; 63
(2019/06/11)
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- Synthesis and evaluation of thiomannosides, potent and orally active FimH inhibitors
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FimH is a type I fimbrial lectin located at the tip of type-1 pili of Gram-negative uropathogenic Escherichia coli (UPEC) guiding its ability to adhere and infect urothelial cells. Accordingly, blocking FimH with small molecule inhibitor is considered as a promising new therapeutic alternative to treat urinary tract infections caused by UPEC. Herein, we report that compounds having the S-glycosidic bond (thiomannosides) had improved metabolic stability and plasma exposures when dosed orally. Especially compound 5h showed the potential to inhibit biofilm formation and also to disrupt the preformed biofilm. And compound 5h showed prophylactic effect in UTI model in mice.
- Sattigeri, Jitendra A.,Garg, Malvika,Bhateja, Pragya,Soni, Ajay,Rauf, Abdul Rehman Abdul,Gupta, Mahendrakumar,Deshmukh, Mahesh S.,Jain, Tarun,Alekar, Nidhi,Barman, Tarani Kanta,Jha, Paras,Chaira, Tridib,Bambal, Ramesh B.,Upadhyay, Dilip J.,Nishi, Takahide
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p. 2993 - 2997
(2018/07/21)
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- SUBSTITUTED NITROGEN CONTAINING COMPOUNDS
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Disclosed are compounds of Formula (I): or a salt thereof, Formula (II) wherein R1 is: or; each W is independently NR1b or O; Z is a bond or CHR1d; and R1, R2, Rd, R3a, R3b, L1, B, V, Y, 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 57; 58; 312
(2019/01/05)
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- New Pyridinones and Isoquinolinones as Inhibitors of the Bromodomain BRD9
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The present invention encompasses compounds of general formula (I) wherein the groups R1 to R9, X1 and X2 have the meanings given in the claims and in the specification. The compounds of the invention are suitable for the treatment of diseases characterized by excessive or abnormal cell proliferation, e.g. cancer, pharmaceutical preparations containing such compounds and their uses as a medicament.
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Paragraph 0459-0460; 0461
(2018/03/25)
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- Iridium-Catalyzed Site-Selective C-H Borylation of 2-Pyridones
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An iridium-catalyzed site-selective C-H borylation of 2-pyridones has been developed. The site selectivity is predominantly controlled by steric factors, and we can access C4, C5, and C6 C-H on the 2-pyridone ring by the judicious choice of ligand and sol
- Miura, Wataru,Hirano, Koji,Miura, Masahiro
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p. 4745 - 4752
(2017/09/30)
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- NOVEL COMPOUNDS AS ROR GAMMA MODULATORS
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The present disclosure is directed to compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein ring A, ring B, L, R1, R2, R3, R4, R5, Ra, Rb, n, m, p and q are as defined herein, which are active as modulators of retinoid-related orphan receptor gamma t (RORγt). These compounds prevent, inhibit, or suppress the action of RORγt and are therefore useful in the treatment of RORγt mediated diseases, disorders, syndromes or conditions such as, e.g., pain, inflammation, COPD, asthma, rheumatoid arthritis, colitis, multiple sclerosis, psoriasis, neurodegenerative diseases and cancer.
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Page/Page column 64
(2017/02/28)
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- BROMODOMAIN INHIBITORS
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The present invention relates to substituted heterocyclic derivative compounds, compositions comprising said compounds, and the use of said compounds and compositions for epigenetic regulation by inhibition of bromodomain-mediated recognition of acetyl lysine regions of proteins, such as histones. Said compositions and methods are useful for the treatment of cancer and neoplastic disease.
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Paragraph 0574; 0575
(2015/04/28)
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- PYRROLOPYRROLONE DERIVATIVES AND THEIR USE AS BET INHIBITORS
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The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof; a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.
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Page/Page column 85; 108
(2015/06/08)
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- PRIMARY CARBOXAMIDES AS BTK INHIBITORS
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The invention provides carboxamide compounds of Formula (I) pharmaceutically acceptable salts, pro-drugs, biologically active metabolites, stereoisomers and isomers thereof wherein the variable are defined herein. The compounds of the invention are useful for treating immunological and oncological conditions, including rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, psoriatic arthritis, psoriasis, ankylosing spondylitis, interstitial cystitis, asthma, systemic lupus erythematosus, lupus nephritis, B cell chronic lymphocytic lymphoma, multiple sclerosis, chronic lymphocytic leukemia, small lymphocytic lymphoma, mantle cell lymphoma, B-cell non-Hodgkin's lymphoma, activated B-celllike diffuse large B-cell, lymphoma, multiple myeloma, diffuse large B-celllymphoma, follicular lymphoma, hairy cell leukemia or Lymphoblastic lymphoma.
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- PYRIDINONE AND PYRIDAZINONE DERIVATIVES
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Compounds of formula (I) wherein A1, A2, A3, A4, J, L, G, and R1 have any of the values defined in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents in the treatment of diseases and conditions, including inflammatory diseases, diabetes, obesity, cancer, and AIDS are disclosed. Pharmaceutical compositions comprising one or more compounds of formula (I) also are disclosed.
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Page/Page column 148
(2014/01/08)
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- PYRROLOPYRIDAZINE JAK3 INHIBITORS AND THEIR USE FOR THE TREATMENT OF INFLAMMATORY AND AUTOIMMUNE DISEASES
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The present invention provides compounds of formula I and pharmaceutically acceptable salts thereof. The formula I compounds inhibit tyrosine kinase activity of JAK3, thereby making them useful for the treatment of inflammatory and autoimmune diseases.
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Page/Page column 212-213
(2012/10/07)
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- COMPOSITIONS AND METHODS FOR MODULATING THE WNT SIGNALING PATHWAY
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The present invention relates to compositions and methods for modulating the Wnt signaling pathway, using compounds having Formula (1) and (3): wherein A, B, Y and Z all represent rings, and R1, R2, R3 are as defined herein.
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Page/Page column 81
(2012/01/15)
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- COMPOUNDS USEFUL AS INHIBITORS OF ATR KINASE
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The present invention relates to pyrazine and pyridine compounds useful as inhibitors of ATR protein kinase. The invention also relates to pharmaceutically acceptable compositions comprising the compounds of this invention; methods of treating various diseases, disorders, and conditions using the compounds of this invention; processes for preparing the compounds of this invention; intermediates for the preparation of the compounds of this invention; and methods of using the compounds in in vitro applications, such as the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors. The compounds of this invention have formula I wherein the variables are as defined herein.
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Page/Page column 57
(2011/12/02)
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- IMIDAZOLE DERIVATIVES AND METHODS OF USE THEREOF
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The present invention relates to novel imidazole compounds, pharmaceutical compositions comprising the imidazole compounds and the use of these compounds for treating or preventing allergy, an allergy-induced airway response, congestion, a cardiovascular disease, an inflammatory disease, a gastrointestinal disorder, a neurological disorder, a metabolic disorder, obesity or an obesity-related disorder, diabetes, a diabetic complication, impaired glucose tolerance or impaired fasting glucose. An illustrative compound of the invention is shown below:
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Page/Page column 22
(2011/06/16)
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- Substituted imidazopyridine, imidazopyrazine, imidazopyridazine and imidazopyrimidine derivatives as melanocortin-4 receptor antagonists
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The present invention relates to substituted imidazopyridine derivatives, imidazopyrazine derivatives, imidazopyridazine derivatives and imidazopyrimidine derivatives according to formula (I) as melanocortin-4 receptor (MC-4R) modulators, in particular as melanocortin-4 receptor antagonists. The antagonists are useful for the treatment of disorders and diseases such as cancer cachexia, muscle wasting, anorexia, emesis, amyotrophic lateral sclerosis (ALS), anxiety and depression.
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Page/Page column 33
(2010/04/25)
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- MODULATORS OF CFTR
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Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette ("ABC") transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator ("CFTR"). The present invention also relates to methods of treating CFTR mediated diseases using compounds of the present invention.
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Page/Page column 96-97
(2009/01/20)
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- FUSED HETEROCYCLIC DERIVATIVES AND METHODS OF USE
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Selected compounds are effective for prophylaxis and treatment of diseases, such as HGF mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving, cancer and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
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Page/Page column 117-118
(2010/11/29)
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