1616100-65-2Relevant articles and documents
Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain Aβ Reduction in Rodents
Wu, Yong-Jin,Guernon, Jason,Yang, Fukang,Snyder, Lawrence,Shi, Jianliang,McClure, Andrea,Rajamani, Ramkumar,Park, Hyunsoo,Ng, Alicia,Lewis, Hal,Chang, ChiehYing,Camac, Dan,Toyn, Jeremy H.,Ahlijanian, Michael K.,Albright, Charles F.,Macor, John E.,Thompson, Lorin A.
, p. 271 - 276 (2016/03/25)
By targeting the flap backbone of the BACE1 active site, we discovered 6-dimethylisoxazole-substituted biaryl aminothiazine 18 with 34-fold improved BACE1 inhibitory activity over the lead compound 1. The cocrystal structure of 18 bound to the active site indicated two hydrogen-bond interactions between the dimethylisoxazole and threonine 72 and glutamine 73 of the flap. Incorporation of the dimethylisoxazole substitution onto the related aminothiazine carboxamide series led to pyrazine-carboxamide 26 as a very potent BACE1 inhibitor (IC50 1 nM). This compound demonstrated robust brain Aβ reduction in rat dose-response studies. Thus, compound 26 may be useful in testing the amyloid hypothesis of Alzheimer's disease.
4,6-DIARYLAMINOTHIAZINES AS BACE1 INHIBITORS AND THEIR USE FOR THE REDUCTION OF BETA-AMYLOID PRODUCTION
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, (2014/07/08)
Compounds of formula (I), including pharmaceutically acceptable salts thereof, are set forth herein: (I) wherein R1 and R2 are independently hydrogen, or -CH3; or R1 and R2 can join together in a ring by adding -(CH2)4-; R3 is hydrogen or C1-C3 al-kyl; Y and Z are independently a C6-C10- aryl group or a 5-10 membered heterocyclic group which can be further substituted with from 0-3 substituents selected from the group of halogen, hydroxy, amino, C1-4 alkylamino, C1-4 dialkylamino, halo C1-4 alkyl, CN, C1-C6, alkyl or cycloalkyl, C1-C6 alkoxy, -C=OC1-4 alkyl, -SO2C1-4 alkyl, and C2-C4 alkynyl; A is selected from the group of phenyl, ben-zyl, oxazolyl, thiazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, and pyrazinyl groups which can be further substituted with from 0-3 substituents selected from the group of halogen, hydroxy, amino, C1-4 alkylamino, C1-4 dialkylamino, haloC1-4 alkyl, hydroxyC1-6 alkyl, CN, C1-C6 alkyl or cycloalkyl, C1-C6 alkoxy, and C2-C4 alkynyl; L is -NHCO-, or is a single bond; and L and Z to-gether can be absent
