JNJ-67569762, A 2-Aminotetrahydropyridine-Based Selective BACE1 Inhibitor Targeting the S3 Pocket: From Discovery to Clinical Candidate

Abstract

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.

In silico and in vitro analyses of a novel FoxO1 agonist reducing Aβ levels via downregulation of BACE1

“…Several small molecules targeting BACE1 have been tested in the clinical trials for the treatment of AD. 45 , 46 , 47 In this study, we found that compound D reduced BACE1 expression levels in a dose‐dependent manner, thereby downregulating Aβ levels. However, compound D had no significant effect on the expression of PS1, a member of the γ‐secretase family of AD‐related genes.…”

“…Many previous reports have indicated that BACE1 is a target for the treatment of AD. Several small molecules targeting BACE1 have been tested in the clinical trials for the treatment of AD 45–47 . In this study, we found that compound D reduced BACE1 expression levels in a dose‐dependent manner, thereby downregulating Aβ levels.…”

Discovery of an Oral, Beyond-Rule-of-Five Mcl-1 Protein–Protein Interaction Modulator with the Potential of Treating Hematological Malignancies

“…73 Chromatography Hydrophobicity Index (CHI). 74 Cassettes containing aliquots of 1 mM compound in DMSO stock solutions to be tested were prepared. An aliquot of a DMSO solution containing a set of 10 calibration compounds with known CHI pH values was added to each cassette to achieve the desired test compound analysis concentration (typically 50 nM).…”

Julia‐Kocienski Olefination in the Synthesis of Trisubstituted Alkenes: Recent Progress

“…Janssen Pharmaceutica carried out the synthesis of several compounds that can be useful for the treatment or prevention of diseases such as cancer. [57] Some of these novel compounds which can serve as myeloid cell leukemia-1 (MCL-1) inhibitors have been synthesized utilizing a Julia-Kocienski olefination approach for the construction of the trisubstituted double bond present in their structure. More specifically, α-fluoro-BT-sulfone 102 reacted with aldehyde 103 in the presence of tBuOK at À 21 °C in THF to afford an E,Z-mixture of fluoro-olefins 104 (Scheme 19).…”