1224944-77-7Relevant articles and documents
Discovery of a novel series of pyrazolo[1,5-a]pyrimidine-based phosphodiesterase 2A inhibitors structurally different from N-((1S)-1-(3-fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915), for the treatment of cognitive disorders
Mikami, Satoshi,Kawasaki, Masanori,Ikeda, Shuhei,Negoro, Nobuyuki,Nakamura, Shinji,Nomura, Izumi,Ashizawa, Tomoko,Kokubo, Hironori,Hoffman, Isaac Dylan,Zou, Hua,Oki, Hideyuki,Uchiyama, Noriko,Hiura, Yuuto,Miyamoto, Maki,Itou, Yuuki,Nakashima, Masato,Iwashita, Hiroki,Taniguchi, Takahiko
, p. 1058 - 1077 (2017)
It has been hypothesized that selective inhibition of phosphodiesterase (PDE) 2A could potentially be a novel approach to treat cognitive impairment in neuropsychiatric and neurodegenerative disorders through augmentation of cyclic nucleotide signaling pathways in brain regions associated with learning and memory. Following our earlier work, this article describes a drug design strategy for a new series of lead compounds structurally distinct from our clinical candidate 2 (TAK-915), and subsequent medicinal chemistry efforts to optimize potency, selectivity over other PDE families, and other preclinical properties including in vitro phototoxicity and in vivo rat plasma clearance. These efforts resulted in the discovery of N-((1S)-2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)-6-methyl-5-(3-methyl-1H-1,2,4triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (20), which robustly increased 3′,5′-cyclic guanosine monophosphate (cGMP) levels in the rat brain following an oral dose, and moreover, attenuated MK-801-induced episodic memory deficits in a passive avoidance task in rats. These data provide further support to the potential therapeutic utility of PDE2A inhibitors in enhancing cognitive performance.
Design and synthesis of Imidazo[1,2-b]pyridazine IRAK4 inhibitors for the treatment of mutant MYD88 L265P diffuse large B-cell lymphoma
Chen, Yun,Bai, Gang,Ning, Yi,Cai, Shi,Zhang, Tao,Song, Peiran,Zhou, Jinpei,Duan, Wenhu,Ding, Jian,Xie, Hua,Zhang, Huibin
supporting information, (2020/02/04)
Harboring MYD88 L265P mutation triggers tumors growth through the activation of NF-κB by interleukin-1 receptor associated kinase 4 (IRAK4) in diffuse large B-cell lymphoma (DLBCL), highlighting IRAK4 as a therapeutic target for tumors driven by aberrant MYD88 signaling. Herein, we report the design, synthesis, and structure?activity relationships of imidazo[1,2-b]pyridazines as potent IRAK4 inhibitors. The representative compound 5 exhibited excellent IRAK4 potency (IRAK4 IC50 = 1.3 nM) and favorable kinase selectivity profile. It demonstrated cellular selectivity for activated B cell–like (ABC) subtype DLBCL with MYD88 L265P mutation in cytotoxicity assay. The kinase inhibitory efficiency of compound 5 was further validated by Western blot analysis of phosphorylation of IRAK4 and downstream signaling in OCI-LY10 and TMD8 cells. Besides, combination of compound 5 and BTK inhibitor ibrutinib synergistically reduced the viability of TMD8 cells. These results indicated that compound 5 could be a promising IRAK4 inhibitor for the treatment of mutant MYD88 DLBCL.
DEGRADERS THAT TARGET ALK AND THERAPEUTIC USES THEREOF
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Paragraph 00199; 00201, (2020/05/12)
Disclosed are bispecific compounds (degraders) that target ALK for degradation. Also disclosed are pharmaceutical compositions containing the degraders and methods of using the compounds to treat diseases and disorders characterized or mediated by aberrant ALK activity