Discovery and Optimization of a Novel Spiropyrrolidine Inhibitor of β-Secretase (BACE1) through Fragment-Based Drug Design

Abstract

The aspartyl protease β-secretase, or BACE, has been demonstrated to be a key factor in the proteolytic formation of Aβ-peptide, a major component of plaques in the brains of Alzheimer's disease (AD) patients, and inhibition of this enzyme has emerged as a major strategy for pharmacologic intervention in AD. An X-ray-based fragment screen of Pfizer's proprietary fragment collection has resulted in the identification of a novel BACE binder featuring spiropyrrolidine framework. Although exhibiting only weak inhibitory activity against the BACE enzyme, the small compound was verified by biophysical and NMR-based methods as a bona fide BACE inhibitor. Subsequent optimization of the lead compound, relying heavily on structure-based drug design and computational prediction of physiochemical properties, resulted in a nearly 1000-fold improvement in potency while maintaining ligand efficiency and properties predictive of good permeability and low P-gp liability.

Ring Opening of Donor–Acceptor Cyclopropanes with the Azide Ion: A Tool for Construction of N‐Heterocycles

“…They also demonstrate moderate cytotoxicity against selected cancer cells 44. Moreover, the ability of the pyrrolidone moiety to undergo selective reduction45 as well as the tendency of the NH 2 group to undergo easy substitution by H or various functional groups through diazonium salt formation enables compound 13 to be transformed into more complex structures of biological relevance 46…”

Advances in the identification of β-secretase inhibitors

“…The small molecular-sized inhibitor 88 (BACE1 IC 50 = 605 nM) was designed from 87. Researchers at Evotec reported the fragment-based BACE1 inhibitor 99 (BACE1 IC 50 = 7 µM, Figure 6D) obtained from a fragment hit compound (BACE1 IC 50 = 770 µM, the structure is not shown in this paper) by SPR [141]. The researchers at Pfizer reported a fragment-based BACE1 inhibitor 100 (NMR IC 50 = 1 µM, Figure 6D) obtained from a hit compound (NMR IC 50 = 1100 µM) with a spiropyrrolidine moiety by fragment screening using the X-ray crystallography strategy [142]. The pyrrolidine portion interacts with two Asp residues at the active site of BACE1 in the crystal structure.…”

Hit Identification and Optimization in Virtual Screening: Practical Recommendations Based on a Critical Literature Analysis

“…Several recently described hit optimization campaigns provide illustrative examples of carefully monitoring key characteristics such as ligand efficiency to generate higher quality leads. 36, 37 …”