1229514-90-2Relevant academic research and scientific papers
JNJ-67569762, A 2-Aminotetrahydropyridine-Based Selective BACE1 Inhibitor Targeting the S3 Pocket: From Discovery to Clinical Candidate
Rombouts, Frederik J. R.,Kusakabe, Ken-Ichi,Alexander, Richard,Austin, Nigel,Borghys, Herman,De Cleyn, Michel,Dhuyvetter, Deborah,Gijsen, Harrie J. M.,Hrupka, Brian,Jacobs, Tom,Jerhaoui, Soufyan,Lammens, Lieve,Leclercq, Laurent,Tsubone, Koichi,Ueno, Tatsuhiko,Morimoto, Kenji,Einaru, Shunsuke,Sumiyoshi, Hirokazu,Van Den Bergh, An,Vos, Ann,Surkyn, Michel,Teisman, Ard,Moechars, Diederik
supporting information, p. 14175 - 14191 (2021/10/12)
The discovery of a novel 2-aminotetrahydropyridine class of BACE1 inhibitors is described. Their pKa and lipophilicity were modulated by a pending sulfonyl group, while good permeability and brain penetration were achieved via intramolecular hydrogen bonding. BACE1 selectivity over BACE2 was achieved in the S3 pocket by a novel bicyclic ring system. An optimization addressing reactive metabolite formation, cardiovascular safety, and CNS toxicity is described, leading to the clinical candidate JNJ-67569762 (12), which gave robust dose-dependent BACE1-mediated amyloid β lowering without showing BACE2-dependent hair depigmentation in preclinical models. We show that 12 has a favorable projected human dose and PK and hence presented us with an opportunity to test a highly selective BACE1 inhibitor in humans. However, 12 was found to have a QT effect upon repeat dosing in dogs and its development was halted in favor of other selective leads, which will be reported in the future.
BICYCLIC HETEROCYCLE DERIVATIVES HAVING SELECTIVE BACE1 INHIBITORY ACTIVITY
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Paragraph 0134, (2019/11/12)
The present invention provides a compound which has an effect of inhibiting amyloid β production, especially an effect of inhibiting selective BACE1, and which is useful as a therapeutic or prophylactic agent for diseases induced by production, secretion and/or deposition of amyloid β proteins. A compound of the formula (IA) or the like, wherein -A1- is alkylene optionally substituted with one or more halogen; R2 is substituted or unsubstituted alkyl or the like; R3 and R4 are each independently a hydrogen atom, halogen, alkyl or haloalkyl or the like; R5 is a hydrogen atom or halogen; A4 is N or CR6 wherein R6 is a hydrogen atom, halogen, or substituted or unsubstituted alkyl; A5 is NR7 or CR8R9; A6 is CR18 or N; R18 is a hydrogen atom; R7 is substituted or unsubstituted alkyl; R8 and R9 are each independently a hydrogen atom, halogen, alkyl or haloalkyl or the like; and Ring B is bicyclic ring; or a pharmaceutically acceptable salt thereof.
5-Amino-2-(1-Hydroxy-Ethyl)-Tetrahydropyran Derivatives
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Page/Page column 20, (2011/10/13)
The invention relates to antibacterial compounds of formula I wherein R1 represents alkoxy (notably methoxy);R2 represents H or F;each of R3, R4, R5 and R6 represents independently H or D;V
5-AMINO-2-(1-HYDROXY-ETHYL)-TETRAHYDROPYRAN DERIVATIVES
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Page/Page column 51, (2010/07/02)
The invention relates to antibacterial compounds of formula I wherein R1 represents alkoxy (notably methoxy); R2 represents H or F; each of R3, R4, R5 and R6 represents independently H or D
