LY-2811376 / Eli Lilly - LARVOL DELTA

DEVELOPING BETA-SECRETASE INHIBITORS FOR TREATMENT OF ALZHEIMER’S DISEASE (ADPD 2022) - "In this paper, AD pathophysiology, beta-secretase structure, BACE1classification, and their correlated adverse and beneficial effects as well as BACE1 inhibitors that are being investigated in clinical trials like LY2811376, LY3314814 (AZD3293) ,CNP520 ,Elenbecestat (E2609) ,Mk8931 (Verubecestat) , LY2886721. The capability of BACE1 to apply such a therapeutic candidate for AD therapy has just been examined during the previous decade. There is proof indicate that the 1 inhibitor administrating time is critical and make big difference in how successful they are in curing AD."

Alzheimer's Disease • CNS Disorders • Cognitive Disorders

Unprecedented polycyclic polyprenylated acylphloroglucinols with anti-Alzheimer's activity from St. John's wort. (PubMed, Chem Sci) - "Compounds 4 and 6 simultaneously displayed notable activation of PP2A (EC: 258.8 and 199.0 nM, respectively) and inhibition of BACE1 in cells (IC: 136.2 and 98.6 nM, respectively), and showed better activities than the positive controls SCR1693 (a PP2A activator, EC: 413.9 nM) and LY2811376 (a BACE1 inhibitor, IC: 260.2 nM). Furthermore, compound 6 showed better therapeutic effects with respect to the reduction of pathological and cognitive impairments in 3 × Tg AD mice than LY2811376. Compound 6 represents the first multitargeted natural product that could activate PP2A and simultaneously inhibit BACE1, which highlights compound 6 as a promising lead compound and a versatile scaffold in AD drug development."

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

Discovery and Early Clinical Development of LY3202626, a Low-Dose, CNS-Penetrant BACE Inhibitor. (PubMed, J Med Chem) - "We have previously reported the clinical development of LY2811376 and LY2886721. LY2886721 advanced to Phase II, but development was halted due to abnormally elevated liver enzymes. Herein, we report the discovery and clinical development of LY3202626, a highly potent, CNS-penetrant, and low-dose BACE inhibitor, which successfully addressed these key development challenges."

Clinical • Journal • Alzheimer's Disease • CNS Disorders

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

Preparation and biological evaluation of BACE1 inhibitors: Leveraging trans-cyclopropyl moieties as ligand efficient conformational constraints. (PubMed, Bioorg Med Chem) - "We previously reported the fragment-based discovery of LY2811376, the first BACE1 inhibitor reported to demonstrate robust reduction of human CSF Aβ in a Phase I clinical trial. We also reported on the discovery of LY2886721, a potent BACE1 inhibitor that reached phase 2 clinical trials. Herein we describe the preparation and structure activity relationships (SAR) of a series of BACE1 inhibitors utilizing trans-cyclopropyl moieties as conformational constraints. The design, details of the stereochemically complex organic synthesis, and biological activity of these BACE1 inhibitors is described."

Journal

Protoilludane, Illudalane, and Botryane Sesquiterpenoids from the Endophytic Fungus Phomopsis sp. TJ507A. (PubMed, J Nat Prod) - "LY2811376 was used as the positive control with an inhibitory activity of 38.6% ( p < 0.01). Furthermore, none of these compounds showed obvious hepatotoxicity at concentration of 40 μM."

Journal

Near-infrared Fluorescence Ocular Imaging (NIRFOI) of Alzheimer's Disease. (PubMed, Mol Imaging Biol) - "The large detection margin by NIRFOI is very important for both diagnosis and therapy response monitoring. Compared to fluorescence microscopic imaging, NIRFOI captures signals with a wide angle (large field of view (FOV)) and can be used to detect soluble Aβs. We believe that NIRFOI has remarkable translational potential for future human studies and can be a potential imaging technology for fast, cheap, accessible, and reliable screening of AD in the future."

Journal

Conformational dynamics of cathepsin D and binding to a small-molecule BACE1 inhibitor. (PubMed, J Comput Chem) - "...Finally, we investigate binding of the inhibitor LY2811376 developed by Eli Lilly to BACE1 and CatD...This work highlights the complexity and challenge in structure-based drug design where receptor-ligand binding induces protonation state change in both the protein and the inhibitor."

Journal