845267-78-9Relevant academic research and scientific papers
Casein kinase 1 (CK1) inhibitor for plants (by machine translation)
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Paragraph 0053; 0056, (2020/02/14)
[Problem] to provide various lead compounds PHA derivatives, and/or circadian rhythm control agent having stronger CK1 inhibitor activity. [Solution] a compound represented by formula I, or a salt thereof or a solvate thereof. (R1 The, H or C1 - 5 A straight-chain, branched or cyclic alkyl group, alkenyl group or alkynyl group, R2 The, H, halogen (F, Cl, Br or I), or a C1 - 4 The alkyl group, the ring A, 5 - 8 membered lactam ring showing; however, R1 And R2 Except H together. )[Drawing] no (by machine translation)
4-Amino-7,8-dihydro-1,6-naphthyridin-5(6 H)-ones as Inhaled Phosphodiesterase Type 4 (PDE4) Inhibitors: Structural Biology and Structure-Activity Relationships
Roberts, Richard S.,Sevilla, Sara,Ferrer, Manel,Taltavull, Joan,Hernández, Bego?a,Segarra, Victor,Gràcia, Jordi,Lehner, Martin D.,Gavaldà, Amadeu,Andrés, Miriam,Cabedo, Judit,Vilella, Dolors,Eichhorn, Peter,Calama, Elena,Carcasona, Carla,Miralpeix, Montserrat
, p. 2472 - 2489 (2018/03/26)
Rational design of a novel template of naphthyridinones rapidly led to PDE4 inhibitors with subnanomolar enzymatic potencies. X-ray crystallography confirmed the binding mode of this novel template. We achieved compounds with double-digit picomolar enzymatic potencies through further structure-based design by targeting both the PDE4 enzyme metal-binding pocket and occupying the solvent-filled pocket. A strategy for lung retention and long duration of action based on low aqueous solubility was followed. In vivo efficacies were measured in a rat lung neutrophilia model by suspension microspray and dry powder administration. Suspension microspray of potent compounds showed in vivo efficacy with a clear dose-response. Despite sustained lung levels, dry powder administration performed much less well and without proper dose-response, highlighting clear differences between the two formulations. This indicates a deficiency in the low aqueous solubility strategy for long duration lung efficacy.
CCR2 MODULATORS
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Paragraph 0268, (2016/12/07)
Compounds are provided that are modulators of the CCR2 receptor. The compounds have the general formula (I) and are useful in pharmaceutical compositions, methods for the treatment of diseases and disorders involving the pathologic activtation of CCR2 receptors.
FUSED THIOPHENE AND THIAZOLE DERIVATIVES AS ROR GAMMA MODULATORS
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, (2015/07/16)
The present invention provides fused thiophene and thiazole derivatives of formula (I), which may be therapeutically useful, more particularly as RORγ modulators; in which R1, R2, R3, R4, R5, R6, R7, X1, X2, L, m, n and ring A have the meanings given in the specification, and pharmaceutically acceptable salts thereof that are useful in the treatment and prevention of diseases or disorders, in particular their use in disease(s) or disorder(s) where there is an advantage in modulating RORγ receptor. The present invention also provides preparation of the compounds and pharmaceutical formulations comprising at least one of the fused thiophene and thiazole derivatives of formula (I), together with a pharmaceutically acceptable carrier, diluent or excipient therefor.
17a-HYDROXYLASE/C17,20-LYASE INHIBITORS
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, (2014/03/21)
The present invention provides compounds of Formula (I), or a pharmaceutically acceptable salt thereof, where R1, R2, R3, R4, R5, R6, A and n are as defined herein. A deuteriated derivative of the compound of Formula (I) is also provided.
HEDGEHOG PATHWAY SIGNALING INHIBITORS AND THERAPEUTIC APPLICATIONS THEREOF
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Paragraph 0144; 0145, (2014/08/06)
The hedgehog (Hh) signaling pathway is a pathway which regulates patterning, growth and cell migration during embryonic development, but in adulthood is limited to tissue maintenance and repair. Mutational inactivation of the inhibitory pathway components leads to constitutive ligand-independent activation of the Hh signaling pathway, results in cancers such as basal cell carcinoma and medulloblastoma. Ligand-dependent activation of Hh signaling is involved in prostate cancer, pancreatic cancer, breast cancer and blood cancers. Therefore, inhibition of the aberrant Hh signaling represents a promising approach toward novel anticancer therapy. The invention provides novel molecules of formula I that inhibit hedgehog pathway signaling and provides therapeutic applications for the treatment of malignancies (basal cell carcinoma, medulloblastoma, glioblastoma, non-small cell lung cancer, prostate cancer, pancreatic cancer, blood cancers, mesenchymal cancers, etc.), prevention of tumor regrowth, sensitization of radio-chemo therapies, and other diseases (inflammation, fibrosis and immune disorders).
A multifaceted secondary structure mimic based on piperidine-piperidinones
Xin, Dongyue,Perez, Lisa M.,Ioerger, Thomas R.,Burgess, Kevin
supporting information, p. 3594 - 3598 (2014/04/17)
Minimalist secondary structure mimics are typically made to resemble one interface in a protein-protein interaction (PPI), and thus perturb it. We recently proposed suitable chemotypes can be matched with interface regions directly, without regard for secondary structures. Here we describe a modular synthesis of a new chemotype 1, simulation of its solution-state conformational ensemble, and correlation of that with ideal secondary structures and real interface regions in PPIs. Scaffold 1 presents amino acid side-chains that are quite separated from each other, in orientations that closely resemble ideal sheet or helical structures, similar non-ideal structures at PPI interfaces, and regions of other PPI interfaces where the mimic conformation does not resemble any secondary structure. 68 different PPIs where conformations of 1 matched well were identified. A new method is also presented to determine the relevance of a minimalist mimic crystal structure to its solution conformations. Thus dld-1-faf crystallized in a conformation that is estimated to be 0.91 kcal-mol-1 above the minimum energy solution state. Do we know, when designing a new peptidomimetic scaffold like the one shown, how it can resemble secondary structures? Design and modular synthesis of this elongated mimic is reported, and the structure is related to ideal and real structures at PPI interfaces.
Heterocycle-to-heterocycle route to quinoline-4-amines: Reductive heterocyclization of 3-(2-nitrophenyl)isoxazoles
Coffman, Keith C.,Duong, Vy,Bagdasarian, Alex L.,Fettinger, James C.,Haddadin, Makhluf J.,Kurth, Mark J.
, p. 7651 - 7657 (2015/04/22)
A variety of quinoline-4-amines were synthesized from substituted 3-(2-nitrophenyl)isoxazoles utilizing Zn0 or Fe0 dust and HOAc using a reductive heterocyclization process. The starting isoxazoles were synthesized from readily available starting materials. A brief survey of functional groups tolerated in this reductive heterocyclization was performed and several 10-amino-3,4-dihydrobenzo[b][1,6]naphthyridin-1(2H)-one and 9-amino-3,4-dihydroacridin-1(2H)-one examples were synthesized.
A modular synthesis of novel 4-amino-7,8-dihydro-1,6-naphthyridin-5(6H)- ones as PDE4 inhibitors
Ferrer, Manel,Roberts, Richard S.,Sevilla, Sara
supporting information, p. 4821 - 4825 (2013/09/02)
A versatile, modular synthetic route to a series of 4-amino-7,8-dihydro-1, 6-naphthyridin-5(6H)-ones has been developed. These compounds represent a novel structural class of potent phosphodiesterase IV (PDE4) inhibitors.
Metal-free, mild, nonepimerizing, chemo- and enantio- or diastereoselective N-alkylation of amines by alcohols via oxidation/imine-iminium formation/reductive amination: A pragmatic synthesis of octahydropyrazinopyridoindoles and higher ring analogues
Khan, Imran A.,Saxena, Anil K.
, p. 11656 - 11669 (2014/01/06)
A mild step and atom-economical nonepimerizing chemo- and enantioselective N-alkylating procedure has been developed via oxidation/imine-iminium formation/reduction cascade using TEMPO-BAIB-HEH-Bronsted acid catalysis in DMPU as solvent and a stoichiometric amount of amine. The optimized conditions were further extended for the nonenzymatic kinetic resolution of the chiral amine thus formed under nonenzymatic in situ hydrogen-transfer conditions using VAPOL-derived phosphoric acid (VAPOL-PA) as the Bronsted acid catalyst. The enantioselective cascade of the presented reaction was successfully utilized in the synthesis of octahydropyrazinopyridoindole and its higher ring analogues.
