Discovery of AM-6494: A Potent and Orally Efficacious β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitor with in Vivo Selectivity over BACE2

Abstract

β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) is an aspartyl protease that plays a key role in the production of amyloid β (Aβ) in the brain and has been extensively pursued as a target for the treatment of Alzheimer's disease (AD). BACE2, an aspartyl protease that is structurally related to BACE1, has been recently reported to be involved in melanosome maturation and pigmentation. Herein, we describe the development of a series of cyclopropylthiazines as potent and orally efficacious BACE1 inhibitors. Lead optimization led to the identification of 20, a molecule with biochemical IC 50 BACE2/BACE1 ratio of 47. Administration of 20 resulted in no skin/fur color change in a 13-day mouse hypopigmentation study and demonstrated robust and sustained reduction of CSF and brain Aβ 40 levels in rat and monkey pharmacodynamic models. On the basis of a compelling data package, 20 (AM-6494) was advanced to preclinical development.

Binding of Inhibitors to BACE1 Affected by pH-Dependent Protonation: An Exploration from Multiple Replica Gaussian Accelerated Molecular Dynamics and MM-GBSA Calculations

“…Because of the important role of BACE1 as a target in the treatment of AD, experimental studies are increasingly focused on the determination of inhibitor–BACE1 complex structures and the development of inhibitors that interrupt the cleavage of APP by BACE1 for use in the clinic; ,− these studies will provide rich structural bases for the design of drugs that target BACE1. Through these experimental studies, the alterations and effect of the environmental pH, which certainly disrupts the activity of BACE1, have been described .…”

One Pot Synthesis of Micromolar BACE-1 Inhibitors Based on the Dihydropyrimidinone Scaffold and Their Thia and Imino Analogues

“…Recently, there has been increasing interest in the development of small, non-peptide inhibitors of the β-amyloid cleaving enzyme 1 (BACE-1, β-secretase) [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ], following the suggestion that this enzyme may be involved in the pathogenesis of Alzheimer’s Disease (AD) [ 19 , 25 ]. BACE-1 is an aspartyl protease involved in the proteolytic degradation of the β-amyloid precursor protein (APP) to form amyloid-β peptide (Aβ), a small protein with a high tendency to form aggregates that are found in the AD brain [ 19 ].…”

Tailored Modeling of Rivastigmine Derivatives as Dual Acetylcholinesterase and Butyrylcholinesterase Inhibitors for Alzheimer's Disease Treatment

“…After designing more than 20 substituents ( Figure 3) of different functional units attached in an N‐methylation pattern to the rivastigmine, we use two web‐based software to filter these derivatives. The N‐substitution premise on a recent study [57] where we modified the scissile bond strength of a newly identified beta‐secretase inhibitor [58] for improved affinity. Selective N‐methylation of amide nitrogen atoms increases the proteolytic stability/bioavailability of peptides [59] .…”