55496-01-0Relevant academic research and scientific papers
New quinoxaline derivatives as dual pim-1/2 kinase inhibitors: Design, synthesis and biological evaluation
Bach, Stéphane,Berthelot, Pascal,Brachet-Botineau, Marie,Croix, Cécile,Denevault-Sabourin, Caroline,Gouilleux, Fabrice,Guillon, Jean,Ibrahim, Sajida,Logé, Cédric,Oyallon, Bruno,Pinaud, No?l,Raoul, William,Robert, Thomas,Viaud-Massuard, Marie-Claude
, (2021/06/12)
Proviral integration site for Moloney murine leukemia virus (Pim)-1/2 kinase overexpression has been identified in a variety of hematologic (e.g., multiple myeloma or acute myeloid leukemia (AML)) and solid (e.g., colorectal carcinoma) tumors, playing a key role in cancer progression, metastasis, and drug resistance, and is linked to poor prognosis. These kinases are thus considered interesting targets in oncology. We report herein the design, synthesis, structure–activity relationships (SAR) and in vitro evaluations of new quinoxaline derivatives, acting as dual Pim1/2 inhibitors. Two lead compounds (5c and 5e) were then identified, as potent submicromolar Pim-1 and Pim-2 inhibitors. These molecules were also able to inhibit the growth of the two human cell lines, MV4-11 (AML) and HCT-116 (colorectal carcinoma), expressing high endogenous levels of Pim-1/2 kinases.
Discovery of 2-[(E)-2-(7-fluoro-3-methylquinoxalin-2-yl)vinyl]-6-pyrrolidin- 1-yl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine hydrochloride as a highly selective PDE10A inhibitor
Kadoh, Yoichi,Miyoshi, Haruko,Matsumura, Takehiko,Tanaka, Yoshihito,Hongu, Mitsuya,Kimura, Mayumi,Takedomi, Kei,Omori, Kenji,Kotera, Jun,Sasaki, Takashi,Kobayashi, Tamaki,Taniguchi, Hiroyuki,Watanabe, Yumi,Kojima, Koki,Sakamoto, Toshiaki,Himiyama, Toshiyuki,Kawanishi, Eiji
, p. 243 - 250 (2018/03/13)
Phosphodiesterase (PDE) 10A is a dual hydrolase of cAMP and cGMP and highly expressed in striatal medium spiny neurons. Inhibition of PDE10A modulates the activity of medium spiny neurons (MSN) via the regulation of cAMP and cGMP. Signal control of MSN is considered associated with psychotic symptoms. Therefore PDE10A inhibitor is expected as a therapeutic method for psychosis disease such as schizophrenia. Avanafil (1) is a PDE5 inhibitor (treatment for erectile dysfunction) discovered by our company. We paid attention to the homology of PDE10A and PDE5 and took advantage of PDE5 inhibitor library to discover PDE10A inhibitors, and found a series of compounds that exhibit higher potency for PDE10A than PDE5. We transformed the afforded derivatives, which had weak inhibitory activity against PDE10A, and discovered stilbene as a PDE10A inhibitor. Brain penetration of this compound was improved by further conversion of N-containing heterocycles and their substituents. The afforded dimethylaminopyrimidine was effective for rat conditioned avoidance response (CAR) test; however, it did not exhibit good brain penetration. We performed in-depth optimization focusing on substituents of the quinoxaline ring, and produced 3-methyl- 7-fluoro quinoxaline. This compound was the most effective in rat CAR test due to its strong PDE10A inhibitory activity and good pharmacokinetics.
Design, synthesis, and AMPA receptor antagonistic activity of a novel 6-nitro-3-oxoquinoxaline-2-carboxylic acid with a substituted phenyl group at the 7 position
Takano, Yasuo,Shiga, Futoshi,Asano, Jun,Ando, Naoki,Uchiki, Hideharu,Fukuchi, Kazunori,Anraku, Tsuyosi
, p. 5841 - 5863 (2007/10/03)
We describe the design, synthesis, and biological properties of a novel series of 7-substituted 6-nitro-3-oxoquinoxaline-2-carboxylic acids. After designing, studying the structure-activity relationships, and evaluating the properties of various compounds
Synthesis and AMPA receptor antagonistic activity of a novel class of quinoxalinecarboxylic acid with a substituted phenyl group at the C-7 position
Takano, Yasuo,Shiga, Futoshi,Asano, Jun,Ando, Naoki,Uchiki, Hideharu,Anraku, Tsuyosi
, p. 3521 - 3525 (2007/10/03)
The synthesis and biological properties of a novel class of 7-heterocycle-substituted quinoxalinecarboxylic acids, which bear a substituted phenyl group through a urethane linkage at the C-7 position, are described. One of the synthesized compounds, 15l,
Synthesis of substituted 2-ethoxycarbonyl- and 2-carboxyquinoxalin -3 ones for evaluation of antimicrobial and anticancer activity
Sanna, Paolo,Carta, Antonio,Loriga, Mario,Zanetti, Stefania,Sechi, Leonardo
, p. 455 - 461 (2007/10/03)
A series of variously substituted quinoxalin-3-ones bearing an ethoxycarbonyl or carboxy group in the C-2 position has been prepared and their structures proved by 1H NMR spectroscopy. The obtained compounds were investigated in vitro for antimicrobial and anticancer activities. Preliminary results showed a moderate activity against a few strains of bacteria but no significant anticancer and anti-HIV activity.
