- PYRIDINYL HETEROCYCLYL COMPOUNDS FOR THE TREATMENT OF AUTOIMMUNE DISEASE
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The present invention relates to compounds of formula (I), a b (I), wherein R1 to R4 and L are as described herein, and their pharmaceutically acceptable salt, enantiomer or diastereomer thereof, and compositions including the compounds and methods of using the compounds.
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Page/Page column 39-40
(2020/01/08)
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- Antimalarial Lead-Optimization Studies on a 2,6-Imidazopyridine Series within a Constrained Chemical Space to Circumvent Atypical Dose-Response Curves against Multidrug Resistant Parasite Strains
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A lead-optimization program around a 2,6-imidazopyridine scaffold was initiated based on the two early lead compounds, 1 and 2, that were shown to be efficacious in an in vivo humanized Plasmodium falciparum NODscidIL2Rγnull mouse malaria infection model. The observation of atypical dose-response curves when some compounds were tested against multidrug resistant malaria parasite strains guided the optimization process to define a chemical space that led to typical sigmoidal dose-response and complete kill of multidrug resistant parasites. After a structure and property analysis identified such a chemical space, compounds were prepared that displayed suitable activity, ADME, and safety profiles with respect to cytotoxicity and hERG inhibition.
- Le Manach, Claire,Paquet, Tanya,Wicht, Kathryn,Nchinda, Aloysius T.,Brunschwig, Christel,Njoroge, Mathew,Gibhard, Liezl,Taylor, Dale,Lawrence, Nina,Wittlin, Sergio,Eyermann, Charles J.,Basarab, Gregory S.,Duffy, James,Fish, Paul V.,Street, Leslie J.,Chibale, Kelly
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p. 9371 - 9385
(2018/10/24)
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- Discovery of piperazinylimidazo[1,2-a]pyridines as novel S4 binding elements for orally active Factor Xa inhibitors
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We have recently reported the discovery of orally active sulfonylalkylamide Factor Xa (FXa) inhibitors, as typified by compound 1 (FXa IC50 = 0.061 μM). Since the pyridylpiperidine moiety was not investigated in our previous study, we conducted detailed structure-activity relationship studies on this S4 binding element. This investigation led to the discovery of piperazinylimidazo[1,2-a]pyridine 2b as a novel and potent FXa inhibitor (FXa IC50 = 0.021 μM). Further modification resulted in the discovery of 2-hydroxymethylimidazo[1,2-a]pyridine 2e (FXa IC50 = 0.0090 μM), which was found to be a selective and orally bioavailable FXa inhibitor with reduced CYP3A4 inhibition.
- Imaeda, Yasuhiro,Kawamoto, Tetsuji,Tobisu, Mamoru,Konishi, Noriko,Hiroe, Katsuhiko,Kawamura, Masaki,Tanaka, Toshimasa,Kubo, Keiji
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p. 3125 - 3140
(2008/09/19)
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