Discovery and Early Clinical Development of LY3202626, a Low-Dose, CNS-Penetrant BACE Inhibitor

McKinzie, David L.; Winneroski, Leonard L.; Green, Steven J.; Hembre, Erik J.; Erickson, Jon A.; Willis, Brian A.; Monk, Scott A.; Aluise, Christopher D.; Baker, Thomas K.; López, José E.; Hendle, J.; Beck, James P.; Brier, Richard A.; Boggs, Leonard N.; Borders, Anthony R.; Cocke, Patrick J; García‐Losada, Pablo; Lowe, Stephen L.; Mathes, Brian M.; May, Patrick C.; Porter, Warren J.; Stout, Stephanie; Timm, David E.; Watson, Brian M.; Yang, Zhihui; Mergott, Dustin J.

doi:10.1021/acs.jmedchem.1c00489

Cited by 15 publications

(5 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To mitigate peripheral effects for tolerability and safety, discovery efforts focused on developing a molecule with high potency against BACE1 and maximizing penetration across the blood-brain barrier [ 21 ]. The IC 50 for LY3202626 in a FRET assay measuring BACE1 activity was 0.615 nM, markedly lower than the value for LY2886721 (20.3 nM) or LY2811376 (239 nM) [ 6, 7 ].…”

Section: Discussionmentioning

confidence: 99%

Robust Pharmacodynamic Effect of LY3202626, a Central Nervous System Penetrant, Low Dose BACE1 Inhibitor, in Humans and Nonclinical Species

Willis

Lowe

Monk

et al. 2022

Journal of Alzheimer's Disease Reports

Self Cite

View full text Add to dashboard Cite

Background: The development of beta-site amyloid-beta precursor protein cleaving enzyme (BACE) 1 inhibitors for the treatment of Alzheimer’s disease requires optimization of inhibitor potency, selectivity, and brain penetration. Moreover, there is a need for low-dose compounds since liver toxicity was found with some BACE inhibitors. Objective: To determine whether the high in vitro potency and robust pharmacodynamic effect of the BACE inhibitor LY3202626 observed in nonclinical species translated to humans. Methods: The effect of LY3202626 versus vehicle on amyloid-β (Aβ) levels was evaluated in a series of in vitro assays, as well as in in vivo and multi-part clinical pharmacology studies. Aβ levels were measured using analytical biochemistry assays in brain, plasma, and cerebrospinal fluid (CSF) of mice, dogs and humans. Nonclinical data were analyzed using an ANOVA followed by Tukey’s post hoc test and clinical data used summary statistics. Results: LY3202626 exhibited significant human BACE1 inhibition, with an IC50 of 0.615±0.101 nM in a fluorescence resonance energy transfer assay and an EC50 of 0.275±0.176 nM for lowering Aβ 1–40 and 0.228±0.244 nM for Aβ 1–42 in PDAPP neuronal cultures. In dogs, CSF Aβ 1hboxx concentrations were significantly reduced by ∼80% at 9 hours following a 1.5 mg/kg dose. In humans, CSF Aβ 1–42 was reduced by 73.1±7.96 % following administration of 6 mg QD. LY3202626 was found to freely cross the blood-brain barrier in dogs and humans. Conclusion: LY3202626 is a potent BACE1 inhibitor with high blood-brain barrier permeability. The favorable safety and pharmacokinetic/pharmacodynamic profile of LY3202626 supports further clinical development.

show abstract

Section: Discussionmentioning

confidence: 99%

Robust Pharmacodynamic Effect of LY3202626, a Central Nervous System Penetrant, Low Dose BACE1 Inhibitor, in Humans and Nonclinical Species

Willis

Lowe

Monk

et al. 2022

Journal of Alzheimer's Disease Reports

Self Cite

View full text Add to dashboard Cite

show abstract

“…In addition to mass spectrometry and NMR spectroscopy, infrared spectroscopy was utilized in this study, in particular, to confirm that M1 is a carbonyl reduction product of tacrolimus.Involvement of gut microbiota in the reductive metabolism was also reported for LY3202626, a β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) inhibitor being assessed as a potential treatment for early Alzheimer's disease. (McKinzie et al, 2021) LY3202626 is converted to M2 which together with M16 are the most abundant metabolites in feces and present as the only source of radioactivity in the feces after 480h following the administration of LY3202626 (Fig. 13).…”

Section: Reductionsmentioning

confidence: 99%

Unusual Biotransformation Reactions of Drugs and Drug Candidates

Isin

2023

Drug Metab Dispos

View full text Add to dashboard Cite

Detailed assessment of the fate of drugs in non-clinical test species and humans is essential to ensure the safety and efficacy of medicines in patients. In this context, biotransformation of drugs and drug candidates has been an area of keen interest over many decades in the pharmaceutical industry as well as academia. Although many of the enzymes and biotransformation pathways involved in the metabolism of xenobiotics and more specifically drugs have been well-characterized, each drug molecule is unique and constitutes specific challenges for the biotransformation scientist. In this mini-review written for the Special Issue on the occasion of the 50 th Anniversary celebration of DMD and to celebrate contributions of Prof. F. Peter Guengerich, one of the pioneers of the drug metabolism field, recently reported "unusual" biotransformation reactions are presented. Scientific and technological advances in the "toolbox" of the biotransformation scientists are summarized. As the pharmaceutical industry continues to explore therapeutic modalities different from the traditional small molecule drugs, the new challenges confronting the biotransformation scientist as well as future opportunities are discussed.

show abstract

“…The bulk of initial BACE1 inhibitors were problematic due to low bioavailability and poor penetration across the blood–brain barrier. Second-generation BACE1 inhibitors (verubecestat [ 177 ], lanabecestat [ 178 ], atabecestat [ 179 ], LY3202626 [ 180 ], umibecestat [ 181 ]and elenbecestat [ 182 ]) were developed to be more lipophilic, and several have entered late-stage clinical trials but failed to show any cognitive or functional benefit in individuals with early AD or mild-to-moderate AD. These inhibitors decrease plasma and CSF Aβ levels and brain plaques but do not demonstrate clinical benefits.…”

Section: App-targeted Treatment Strategies In Admentioning

confidence: 99%

Amyloid Precursor Protein: A Regulatory Hub in Alzheimer's Disease

2023

Aging dis

View full text Add to dashboard Cite

Decades of research have demonstrated an incontrovertible role of amyloid-β (Aβ) in the etiology of Alzheimer's disease (AD). However, the overemphasis on the pathological impacts of Aβ may obscure the role of its metabolic precursor, amyloid precursor protein (APP), as a significant hub in the occurrence and progression of AD. The complicated enzymatic processing, ubiquitous receptor-like properties, and abundant expression of APP in the brain, as well as its close links with systemic metabolism, mitochondrial function and neuroinflammation, imply that APP plays multifaceted roles in AD. In this review, we briefly describe the evolutionarily conserved biological characteristics of APP, including its structure, functions and enzymatic processing. We also discuss the possible involvement of APP and its enzymatic metabolites in AD, both detrimental and beneficial. Finally, we describe pharmacological agents or genetic approaches with the capability to reduce APP expression or inhibit its cellular internalization, which can ameliorate multiple aspects of AD pathologies and halt disease progression. These approaches provide a basis for further drug development to combat this terrible disease.

show abstract

Discovery and Early Clinical Development of LY3202626, a Low-Dose, CNS-Penetrant BACE Inhibitor

Cited by 15 publications

References 50 publications

Robust Pharmacodynamic Effect of LY3202626, a Central Nervous System Penetrant, Low Dose BACE1 Inhibitor, in Humans and Nonclinical Species

Robust Pharmacodynamic Effect of LY3202626, a Central Nervous System Penetrant, Low Dose BACE1 Inhibitor, in Humans and Nonclinical Species

Unusual Biotransformation Reactions of Drugs and Drug Candidates

Amyloid Precursor Protein: A Regulatory Hub in Alzheimer's Disease

Contact Info

Product

Resources

About