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.
BICYCLIC HETEROCYCLE DERIVATIVES HAVING SELECTIVE BACE1 INHIBITORY ACTIVITY
-
, (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.
GEMINAL SUBSTITUTED QUINUCLIDINE AMIDE COMPOUNDS AS AGONISTS OF ALPHA-7 NICOTINIC ACETYLCHOLINE RECEPTORS
-
, (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
-
Page/Page column 22, (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
-
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
ANTIBACTERIAL AGENTS
-
Page/Page column 37, (2010/11/25)
Naphthalene, quinoline, quinoxaline and naphthyridine derivatives useful in the treatment of bacterial infections in mammals, particularly humans, are disclosed herein.
ANTIBACTERIAL AGENTS
-
Page/Page column 36, (2010/10/20)
Naphthalene, quinoline, quinoxaline and naphthyridine derivatives useful in the treatment of bacterial infections in mammals, particularly humans, are disclosed herein.
Design, synthesis, structure-activity relationship, and in vivo activity of azabicyclic aryl amides as α7 nicotinic acetylcholine receptor agonists
Walker, Daniel P.,Wishka, Donn G.,Piotrowski, David W.,Jia, Shaojuan,Reitz, Steven C.,Yates, Karen M.,Myers, Jason K.,Vetman, Tatiana N.,Margolis, Brandon J.,Jacobsen, E. Jon,Acker, Brad A.,Groppi, Vincent E.,Wolfe, Mark L.,Thornburgh, Bruce A.,Tinholt, Paula M.,Cortes-Burgos, Luz A.,Walters, Rodney R.,Hester, Matthew R.,Seest, Eric P.,Dolak, Lester A.,Han, Fusen,Olson, Barbara A.,Fitzgerald, Laura,Staton, Brian A.,Raub, Thomas J.,Hajos, Mihaly,Hoffmann, William E.,Li, Kai S.,Higdon, Nicole R.,Wall, Theron M.,Hurst, Raymond S.,Wong, Erik H.F.,Rogers, Bruce N.
, p. 8219 - 8248 (2007/10/03)
A novel set of azabicyclic aryl amides have been identified as potent and selective agonists of the α7 nAChR. A two-pronged approach was taken to improve the potential hERG liability of previously disclosed α7 nAChR agonist, PNU-282,987, while maintaining the compound's other desirable pharmacological properties. The first approach involved further exploration of the aryl carboxylic acid fragment of PNU-282,987, while the second approach focused on modification of the azabicyclic amine portion of PNU-282,987. The best compounds from each series are characterized by rapid brain penetration, good oral bioavailability in rat, and demonstrate in vivo efficacy in a rat P50 auditory sensory gating assay. At least one analog from each series (1h, 1o, 2a, 9a, and 18a) shows an improved hERG safety profile over PNU-282,987.
