527681-13-6Relevant articles and documents
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
, 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.
GEMINAL SUBSTITUTED QUINUCLIDINE AMIDE COMPOUNDS AS AGONISTS OF ALPHA-7 NICOTINIC ACETYLCHOLINE RECEPTORS
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, (2016/07/05)
The present invention relates to novel geminal substituted quinuclidine amide compounds, and pharmaceutical compositions of the same, that are suitable as agonists or partial agonists of α7- nAChR, and methods of preparing these compounds and compositions, and the use of these compounds and compositions in methods of maintaining, treating and/or improving cognitive function. In particular, methods of administering the compound or composition to a patient in need thereof, for example a patient with a cognitive deficiency and/or a desire to enhance cognitive function, that may derive a benefit therefrom.
5-AMINO-2-(1-HYDROXY-ETHYL)-TETRAHYDROPYRAN DERIVATIVES
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Page/Page column 58, (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
