NB-360 / Novartis - LARVOL DELTA

Evaluating the impact of age and treatment on neuroinflammation-related proteins in mouse models of proteinopathies. (PubMed, Exp Neurol) - "TREM2, Axl, galectin-3, Aβ, and cytokines were measured by immunoassays in brain homogenates from WT, AppNL-G-F, tg-ArcSwe, and tg-UppSwe mice across four age groups and from mice subjected to three treatment strategies targeting Aβ (beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor NB-360 and antibody RmAb158) or α-synuclein (antibody RmAb38E2)...In summary, microglial TREM2, Axl, and galectin-3 are promising biomarkers for tracking AD-related neuroinflammation. Microglial interactions with Aβ likely influence the outcomes of Aβ-targeting therapies, and characterizing their dynamic states will inform the development of diagnostic tools and treatments relying on microglial activation to alleviate pathologies associated with neurodegenerative diseases."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Inflammation • Proteinopathy • AXL

Revealing the binding mechanism of BACE1 inhibitors through molecular dynamics simulations. (PubMed, J Biomol Struct Dyn) - "This study employs molecular dynamics simulations and binding energy analysis to investigate the binding interactions between BACE1 and four selected small molecules: CNP520, D9W, NB641, and NB360. Hydrogen bond analysis reveals a limited number of bonds between BACE1 and each small molecule, highlighting the importance of structural modifications to enable more stable hydrogen bonds. This research provides valuable insights into the molecular mechanisms of potential Alzheimer's disease therapeutics, guiding the way for improved drug design and the development of effective treatments targeting BACE1.Communicated by Ramaswamy H. Sarma."

Journal • Alzheimer's Disease • CNS Disorders

"@WHO are in disagreement with the @US_FDA @paulturner2012 @StaceyOIrish @HoaxMiddle @robhartley1974 @michaelpbreton @flygirlie30 @LesleyMillercyp @SaiKate108 @juneslater17 @InspoCrypto @sophiadahl1 @HolyRage2030 @ClarkieThomson @SusanBe36094276 https://t.co/roP9EQ353v" (@BenAltstein)

β-secretase inhibition prevents structural spine plasticity deficits in App mice. (PubMed, Front Aging Neurosci) - "We conducted in vivo two-photon microscopy in the stratum oriens layer of hippocampal CA1 neurons in 3.5-month-old App GFP-M mice over 6 weeks to monitor the effect of potential preventive treatment with a high and low dose of the BACE1-inhibitor NB-360 on dendritic spine dynamics...Prolonged high-dose BACE1-inhibition significantly enhanced spine formation, improving spine dynamics in the AD mouse model. We conclude that in an early AD stage characterized by low Aβ-accumulation and no irreversible spine loss, BACE1-inhibition could hold the progressive synapse loss and cognitive decline by improving structural spine dynamics."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders

Discovery of Umibecestat (CNP520): A Potent, Selective, and Efficacious β-Secretase (BACE1) Inhibitor for the Prevention of Alzheimer's Disease. (PubMed, J Med Chem) - "Insertion of a methyl and a trifluoromethyl group at the 6-position of the 5-amino-1,4-oxazine led to 8 (NB-360), an inhibitor with a pK of 7.1, a very low P-glycoprotein efflux ratio, and excellent pharmacological profile, enabling high central nervous system penetration and exposure. Herein, we describe the steps leading to the discovery of 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide 15 (CNP520, umibecestat), an inhibitor with superior BACE1/BACE2 selectivity and pharmacokinetics. CNP520 reduced significantly Aβ levels in mice and rats in acute and chronic treatment regimens without any side effects and thus qualified for Alzheimer's disease prevention studies in the clinic."

Journal • Alzheimer's Disease • CNS Disorders

C-PIB and I-antibody PET provide differing estimates of brain amyloid-beta after therapeutic intervention. (PubMed, J Nucl Med) - " Transgenic ArcSwe mice (16 months) were treated with the BACE-1 inhibitor NB-360 for 2 months, while another group was kept as controls... This study demonstrated the ability of an antibody-based radioligand to detect changes in brain Aβ levels after anti-Aβ therapy in ArcSwe and AppNL-G-F mice with pronounced Aβ pathology. In contrast, the decreased Aβ levels could not be quantified with C-PiB PET, suggesting that these ligands detect different pools of the Aβ."

Journal • Alzheimer's Disease • CNS Disorders

Synthesis of the Potent, Selective, and Efficacious β-Secretase (BACE1) Inhibitor NB-360. (PubMed, J Med Chem) - "Various synthetic routes to access BACE1 inhibitors bearing a 5-amino-6-methyl-6-(trifluoromethyl)-1,4-oxazine headgroup were investigated. Subsequent optimization of the P3 fragment provided the highly potent N-(3-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide 54 (NB-360), able to reduce significantly Aβ levels in mice, rats, and dogs in acute and chronic treatment regimens."

Journal

Selective Secretase Targeting for Alzheimer's Disease Therapy. (PubMed, J Alzheimers Dis) - "In this regard, BACE-1 inhibitors, such as Atabecestat, NB-360, Umibecestat, PF-06751979, Verubecestat, LY2886721, Lanabecestat, LY2811376, and Elenbecestat, were submitted to phase I-III clinical trials. Such therapeutic tools shall focus on slowing down or minimizing the progression of neuronal damage. Here, we summarize structures and the activities of the latest compounds designed for AD treatment, with remarkable in vitro, in vivo, and clinical phase activities."

Journal • Review • Alzheimer's Disease • CNS Disorders

The BACE inhibitor NB-360 in preclinical models: From β-amyloid reduction to downstream disease-relevant effects. (PubMed, Br J Pharmacol) - "NB-360 effects on the processing of physiological BACE-1 substrates as well as on non-enzymatic BACE-1 functions have been investigated and complement studies performed with BACE-1 knock-out mice. Since NB-360 is also an inhibitor for BACE-2, non-clinical studies in adult animals revealed physiological effects of BACE-2 inhibition."

Journal • Preclinical • Review • Alzheimer's Disease • CNS Disorders • Dementia • Immunology • Inflammation

β-secretase BACE1 is required for normal cochlear function. (PubMed, J Neurosci) - "To determine whether the cochlea of adult wild-type mice is susceptible to AD treatment-like suppression of BACE1, we administered the established BACE1 inhibitor NB-360 for 6 weeks...We relate this deficit to impaired myelination and aberrant synapse formation in the cochlea, which manifest during postnatal development. By contrast, prolonged pharmacological suppression of BACE1 activity in adult wild type mice did not reproduce the hearing deficit or the cochlear abnormalities of BACE1 null mice."

Journal • Alzheimer's Disease • CNS Disorders

Antibody-based in vivo PET imaging detects amyloid-β reduction in Alzheimer transgenic mice after BACE-1 inhibition. (PubMed, J Nucl Med) - "A second set of tg-ArcSwe mice, aged 10 mo, were treated with the BACE-1 inhibitor NB-360 for 3 mo and compared with an untreated control group... A number of treatments for AD are currently studied in phase 2 and 3 clinical trials but there are limited possibilities to study their effects on the important, non-fibrillar Aβ forms in vivo. This study demonstrates the ability of the Aβ protofibril selective radioligand [I]RmAb158-scFv8D3 to follow disease progression and detect treatment effects with PET imaging in tg-ArcSwe mice."

Journal • Preclinical

Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibition Impairs Synaptic Plasticity via Seizure Protein 6. (PubMed, Biol Psychiatry) - "Our results suggest that SEZ6 plays an important role in maintaining normal dendritic spine dynamics. Furthermore, SEZ6 is involved in BACE1 inhibition-induced structural and functional synaptic alterations."

Journal

EFFECT OF CHRONIC BACE1 INHIBITION ON HIPPOCAMPAL SPINE PLASTICITY DISTAL AND PROXIMAL TO PLAQUES IN APPNL-G-F-MICE (ADPD 2019) - " Our MWM-Test data indicates that NB360 treatment improves the memory deficits seen in APPNL-G-F-mice. Furthermore, we assume that treatment with carefully dosed NB360 will also lead to a normalization of the decreased dynamics of postsynaptic structures adjacent to amyloid plaques without affecting dendritic spine plasticity distant from plaques."

Preclinical

BACE1 INHIBITION PREFERENTIALLY BLOCKS PLAQUE FORMATION AND SLOWS DOWN β-AMYLOID RELATED AXONAL PATHOLOGY AND SYNAPSE LOSS (ADPD 2019) - "... We investigated the impact of early BACE1 inhibition on the dynamics of amyloid, axonal and presynaptic pathology in APPPS1 mice using time-lapse in vivo two-photon imaging In APPPS1 mice pharmacological treatment with the potent, small-molecule BACE1 inhibitor NB-360 fails to revert but significantly reduces the progressive amyloid deposition and mitigates presynaptic pathology... The results strongly imply presymptomatic application of BACE1 inhibitors before amyloid deposition has reached an asymptote of accumulation to achieve optimum efficacy. Since our data indicates that BACE1 accumulation around plaques significantly contributes to further Aβ deposition, targeting plaque-associated axonal damage could emerge as a suitable strategy not only in treating synapse loss but also to target Aβ accumulation itself."