Discovery of an Orally Available, Brain Penetrant BACE1 Inhibitor That Affords Robust CNS Aβ Reduction

Abstract

Inhibition of BACE1 to prevent brain Aβ peptide formation is a potential disease-modifying approach to the treatment of Alzheimer’s disease. Despite over a decade of drug discovery efforts, the identification of brain-penetrant BACE1 inhibitors that substantially lower CNS Aβ levels following systemic administration remains challenging. In this report we describe structure-based optimization of a series of brain-penetrant BACE1 inhibitors derived from an iminopyrimidinone scaffold. Application of structure-based design in tandem with control of physicochemical properties culminated in the discovery of compound 16, which potently reduced cortex and CSF Aβ40 levels when administered orally to rats.

Constant pH Molecular Dynamics Reveals pH-Modulated Binding of Two Small-Molecule BACE1 Inhibitors

“…B. Iminopyrimidinone-based inhibitor 1 discovered by Merck (MK8698). 7 C. Aminothiazine-based inhibitor 2 discovered by Eli Lilly (LY2811376). 8 The two endo- and exocyclic amines on the ABM are highlighted by a red rectangle.…”

“…The pH-induced dissociation of 2 is a consequence of the protonation of Asp32 and offers an explanation for the significantly reduced binding affinity and activity of 2 when measured under the most active pH condition of the enzyme. 7,8 We note that, since dissociation of the inhibitor occurs on a longer time scale compared to our limited simulation length, the fraction of unbound configurations shown in Figure 3C is likely not quantitative. However, a quantitative prediction of binding affinity is not in the scope of the current work as the simulation length required for absolute convergence of the entire ensemble of unbound configurations is prohibitively expensive.…”

“…Inhibitor 1 7 closely resembles the Merck inhibitor MK8931 currently under phase 2/3 clinical trial, 2 while inhibitor 2 was discovered by Eli Lilly and tested in preclinical animal models and humans but discontinued due to retinal toxicity. 8 Recently, structure-based optimization has been applied to 2 by Pfizer in an effort to reduce toxicity.…”

“…To explore the interactions of the two inhibitors with BACE1 in the enzyme active pH range, we performed constant pH molecular dynamics (pHMD) simulations starting from the crystal structures of BACE1 complexed with 1 and 2 (PDB ID 4FRS 7 and 4YBI 8 , respectively). Previous pHMD simulations and Born approximation methods have been utilized to predict shifts in the BACE1 catalytic dyad p K a with neutral peptide-like inhibitors, while this work considers charged small molecules that change protonation state as a function of pH.…”

Design and Validation of Bicyclic Iminopyrimidinones As Beta Amyloid Cleaving Enzyme-1 (BACE1) Inhibitors: Conformational Constraint to Favor a Bioactive Conformation

“…Details of the protocols for X-ray crystallography, aspartyl protease K i , and cell Aβ40 IC 50 assays and in vivo rat CSF studies can be found in ref 21.…”