- Discovery of 3-(4-(2-((1 H-Indol-5-yl)amino)-5-fluoropyrimidin-4-yl)-1 H-pyrazol-1-yl)propanenitrile Derivatives as Selective TYK2 Inhibitors for the Treatment of Inflammatory Bowel Disease
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TYK2 mediates signaling of IL-23, IL-12, and Type I IFN-driven responses that are critical in immune-mediated diseases. Herein, we report the design, synthesis, and structure-activity relationships (SARs) of 3-(4-(2-((1H-indol-5-yl)amino)-5-fluoropyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile derivatives as selective TYK2 inhibitors. Among them, compound 14l exhibited acceptable TYK2 inhibition with an IC50 value of 9 nM, showed satisfactory selectivity characteristics over the other three homologous JAK kinases, and performed good functional potency in the JAK/STAT signaling pathway on lymphocyte lines and human whole blood. In liver microsomal assay studies, the clearance rate and half-life of 14l were 11.4 mL/min/g and 121.6 min, respectively. Furthermore, in a dextran sulfate sodium colitis model, 14l reduced the production of pro-inflammatory cytokines IL-6 and TNF-α and improved the inflammation symptoms of mucosal infiltration, thickening, and edema. Taken together, 14l was a selective TYK2 inhibitor and could be used to treat immune diseases deserving further investigation.
- Zhang, Chufeng,Qi, Wenyan,Li, Yong,Tang, Minghai,Yang, Tao,Liu, Kongjun,Chen, Yong,Deng, Dexin,Xiang, Mingli,Xiang, Mingli,Chen, Lijuan
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- Palladium-catalyzed reduction of N-(tert-Butoxycarbonyl)indoles by polymethylhydrosiloxane
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The palladium-catalyzed [10% Pd(OH)2/C] reduction of N-(tert-butoxycarbonyl)indoles to the corresponding N-(tert-butoxycarbonyl) indolines is described. Polymethylhydrosiloxane was used as reducing agent and the reaction proceeded smoothly at r
- Chandrasekhar, Srivari,Basu, Debjit,Reddy, Ch. Raji
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- Synthesis and Pharmacological Characterization of Conformationally Restricted Retigabine Analogues as Novel Neuronal Kv7 Channel Activators
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Kv7 K+ channels represent attractive pharmacological targets for the treatment of different neurological disorders, including epilepsy. In this paper, 42 conformationally restricted analogues of the prototypical Kv7 activator retigabine have been synthesized and tested by electrophysiological patch-clamp experiments as Kv7 agonists. When compared to retigabine (0.93 ± 0.43 μM), the EC50s for Kv7.2 current enhancements by compound 23a (0.08 ± 0.04 μM) were lower, whereas no change in potency was observed for 24a (0.63 ± 0.07 μM). In addition, compared to retigabine, 23a and 24a showed also higher potency in activating heteromeric Kv7.2/Kv7.3 and homomeric Kv7.4 channels. Molecular modeling studies provided new insights into the chemical features required for optimal interaction at the binding site. Stability studies evidenced improved chemical stability of 23a and 24a in comparison with retigabine. Overall, the present results highlight that the N5-alkylamidoindole moiety provides a suitable pharmacophoric scaffold for the design of chemically stable, highly potent and selective Kv7 agonists.
- Ostacolo, Carmine,Miceli, Francesco,Di Sarno, Veronica,Nappi, Piera,Iraci, Nunzio,Soldovieri, Maria Virginia,Ciaglia, Tania,Ambrosino, Paolo,Vestuto, Vincenzo,Lauritano, Anna,Musella, Simona,Pepe, Giacomo,Basilicata, Manuela Giovanna,Manfra, Michele,Perinelli, Diego Romano,Novellino, Ettore,Bertamino, Alessia,Gomez-Monterrey, Isabel M.,Campiglia, Pietro,Taglialatela, Maurizio
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p. 163 - 185
(2020/01/09)
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- LACTAM-CONTAINING COMPOUNDS AND DERIVATIVES THEREOF AS FACTOR XA INHIBITORS
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The present application describes lactam-containing compounds and derivatives thereof of Formula I: P4—P-M-M4??I or pharmaceutically acceptable salt forms thereof, wherein ring P, if present is a 5-7 membered carbocycle or heterocycle and ring M is a 5-7 membered carbocycle or heterocycle. Compounds of the present invention are useful as inhibitors of trypsin-like serine proteases, specifically factor Xa.
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- FUSED HETEROCYCLIC COMPOUNDS
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The present invention provides a compound which has the effect of PDE inhibition, and which is useful as an agent for preventing or treating schizophrenia. The compound is represented by the formula (I): wherein the symbols are defined in the specification.
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- SUBSTITUTED ARYLSULFONYLAMINOMETHYLPHOSPHONIC ACID DERIVATIVES, THEIR PREPARATION AND THEIR USE IN THE TREATMENT OF TYPE I AND II DIABETES MELLITUS
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The present invention relates to substituted arylsulphonylaminomethylphosphonic acid derivatives of general formula (I) wherein R, X, Y and Z are defined as in claim 1, the tautomers, enantiomers, diastereomers, mixtures thereof and salts thereof which ha
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Page/Page column 54
(2009/03/07)
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- QUINAZOLINONE AND FUSED PYRIMIDINONE COMPOUNDS AND THEIR USE IN TREATING SODIUM CHANNEL-MEDIATED DISEASES OR CONDITIONS
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This invention is directed to compounds of formula (I): wherein (A), n, R1, R2 and R3 are as defined herein, as a stereoisomer, enantiomer, tautomer thereof or mixtures thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof, for the treatment and/or prevention of sodium channel-mediated diseases or conditions, such as pain.
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Page/Page column 92-93
(2008/12/07)
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- NEW SUBSTITUTED ARYLSULPHONYLGLYCINES, THE PREPARATION THEREOF AND THE USE THEREOF AS PHARMACEUTICAL COMPOSITIONS
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The present invention relates to substituted arylsulphonylglycines of general formula (I) wherein R, X, Y and Z are defined as in claim 1, the tautomers, enantiomers, diastereomers, mixtures thereof and salts thereof, which have valuable pharmacological properties, particularly the suppression of the interaction of glycogen phosphorylase a with the GL subunit of glycogen-associated protein phosphatase 1 (PP1 ), and their use as pharmaceutical compositions.
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Page/Page column 92
(2008/12/07)
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- THIENOPYRAZOLE DERIVATIVE HAVING PDE7 INHIBITORY ACTIVITY
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To provide thienopyrazole derivatives inhibiting PDE 7 selectively, and therefore, enhance cellular cAMP level. Consequently, the compound is useful for treating various kinds of disease such as allergic diseases, inflammatory diseases or immunologic diseases. The compound is thienopyrazole compound represented by the following formula (I): [wherein, especially, R 1 is a cyclohexyl, a cycloheptyl group or a tetrahydropyranyl group; R 2 is methyl; R 3 is a hydrogen atom; and R 4 is a group: -CONR 5 R 6 (in which any one of R 5 and R 6 is a hydrogen atom)].
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(2008/06/13)
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- Design, structure-activity relationship, and pharmacokinetic profile of pyrazole-based indoline factor Xa inhibitors
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A new series of pyrazole-based factor Xa inhibitors have been identified as part of our ongoing efforts to optimize previously reported clinical candidate razaxaban. Concern over the possible formation of primary aniline metabolites via amide hydrolysis led to the replacement of the primary amide linker between the pyrazole and phenyl moieties with secondary amides. This was accomplished by replacing the aniline with a variety of heterobicycles, of which indolines were the most potent. The indoline series demonstrated subnanomolar factor Xa binding Kis, modest to high selectivity versus other serine proteases, and good in vitro clotting activity. A small number of indoline fXa inhibitors were profiled in a dog pharmacokinetic model, one of which demonstrated pharmacokinetic parameters similar to that of clinical candidate razaxaban.
- Varnes, Jeffrey G.,Wacker, Dean A.,Jacobson, Irina C.,Quan, Mimi L.,Ellis, Christopher D.,Rossi, Karen A.,He, Ming Y.,Luettgen, Joseph M.,Knabb, Robert M.,Bai, Steven,He, Kan,Lam, Patrick Y.S.,Wexler, Ruth R.
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p. 6481 - 6488
(2008/03/18)
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- Lactam-containing compounds and derivatives thereof as factor Xa inhibitors
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The present application describes lactam-containing compounds and derivatives thereof of Formula I: or pharmaceutically acceptable salt forms thereof, wherein ring P, if present is a 5-7 membered carbocycle or heterocycle and ring M is a 5-7 membered carbocycle or heterocycle. Compounds of the present invention are useful as inhibitors of trypsin-like serine proteases, specifically factor Xa.
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