161468-45-7Relevant articles and documents
Design and Discovery of N-(3-(2-(2-Hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide, a Selective, Efficacious, and Well-Tolerated RAF Inhibitor Targeting RAS Mutant Cancers: The Path to the Clinic
Ramurthy, Savithri,Taft, Benjamin R.,Aversa, Robert J.,Barsanti, Paul A.,Burger, Matthew T.,Lou, Yan,Nishiguchi, Gisele A.,Rico, Alice,Setti, Lina,Smith, Aaron,Subramanian, Sharadha,Tamez, Victoriano,Tanner, Huw,Wan, Lifeng,Hu, Cheng,Appleton, Brent A.,Mamo, Mulugeta,Tandeske, Laura,Tellew, John E.,Huang, Shenlin,Yue, Qin,Chaudhary, Apurva,Tian, Hung,Iyer, Raman,Hassan, A. Quamrul,Mathews Griner, Lesley A.,La Bonte, Laura R.,Cooke, Vesselina G.,Van Abbema, Anne,Merritt, Hanne,Gampa, Kalyani,Feng, Fei,Yuan, Jing,Mishina, Yuji,Wang, Yingyun,Haling, Jacob R.,Vaziri, Sepideh,Hekmat-Nejad, Mohammad,Polyakov, Valery,Zang, Richard,Sethuraman, Vijay,Amiri, Payman,Singh, Mallika,Sellers, William R.,Lees, Emma,Shao, Wenlin,Dillon, Michael P.,Stuart, Darrin D.
, p. 2013 - 2027 (2020)
Direct pharmacological inhibition of RAS has remained elusive, and efforts to target CRAF have been challenging due to the complex nature of RAF signaling, downstream of activated RAS, and the poor overall kinase selectivity of putative RAF inhibitors. Herein, we describe 15 (LXH254, Aversa, R.; et al. Int. Patent WO2014151616A1, 2014), a selective B/C RAF inhibitor, which was developed by focusing on drug-like properties and selectivity. Our previous tool compound, 3 (RAF709; Nishiguchi, G. A.; et al. J. Med. Chem. 2017, 60, 4969), was potent, selective, efficacious, and well tolerated in preclinical models, but the high human intrinsic clearance precluded further development and prompted further investigation of close analogues. A structure-based approach led to a pyridine series with an alcohol side chain that could interact with the DFG loop and significantly improved cell potency. Further mitigation of human intrinsic clearance and time-dependent inhibition led to the discovery of 15. Due to its excellent properties, it was progressed through toxicology studies and is being tested in phase 1 clinical trials.
Rational Design, Pharmacomodulation, and Synthesis of Dual 5-Hydroxytryptamine 7 (5-HT7)/5-Hydroxytryptamine 2A (5-HT2A) Receptor Antagonists and Evaluation by [18F]-PET Imaging in a Primate Brain
Deau, Emmanuel,Robin, Elodie,Voinea, Raluca,Percina, Nathalie,Sata?a, Grzegorz,Finaru, Adriana-Luminita,Chartier, Agnès,Tamagnan, Gilles,Alagille, David,Bojarski, Andrzej J.,Morisset-Lopez, Séverine,Suzenet, Franck,Guillaumet, Gérald
, p. 8066 - 8096 (2015/11/09)
We report the synthesis of 46 tertiary amine-bearing N-alkylated benzo[d]imidazol-2(3H)-ones, imidazo[4,5-b]pyridin-2(3H)-ones, imidazo[4,5-c]pyridin-2(3H)-ones, benzo[d]oxazol-2(3H)-ones, oxazolo[4,5-b]pyridin-2(3H)-ones and N,N′-dialkylated benzo[d]imidazol-2(3H)-ones. These compounds were evaluated against 5-HT7R, 5-HT2AR, 5-HT1AR, and 5-HT6R as potent dual 5-HT7/5-HT2A serotonin receptors ligands. A thorough study of the structure-activity relationship of the aromatic rings and their substituents, the alkyl chain length and the tertiary amine was conducted. 1-(4-(4-(4-Fluorobenzoyl)piperidin-1-yl)butyl)-1H-benzo[d]imidazol-2(3H)-one (79) and 1-(6-(4-(4-fluorobenzoyl)piperidin-1-yl)hexyl)-1H-benzo[d]imidazol-2(3H)-one (81) were identified as full antagonist ligands on cyclic adenosine monophosphate (cAMP, KB = 4.9 and 5.9 nM, respectively) and inositol monophosphate (IP1, KB = 0.6 and 16 nM, respectively) signaling pathways of 5-HT7R and 5-HT2AR. Both antagonists crossed the blood-brain barrier as evaluated with [18F] radiolabeled compounds [18F]79 and [18F]81 in a primate's central nervous system using positron emission tomography. Both radioligands showed standard uptake values ranging from 0.8 to 1.1, a good plasmatic stability, and a distribution consistent with 5-HT7R and 5-HT2AR in the CNS.
CYCLOHEXYL AMIDE DERIVATIVES AS CRF RECEPTOR ANTAGONISTS
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Page/Page column 93, (2016/02/02)
There are described cydohexyl amide derivatives useful as corticotropin releasing factor (CRF) receptor antagonists
