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

Abstract

On the basis of our observation that the biaryl substituent of iminopyrimidinone 7 must be in a pseudoaxial conformation to occupy the contiguous S1-S3 subsites of BACE1, we have designed a novel fused bicyclic iminopyrimidinone scaffold intended to favor this bioactive conformation. Strategic incorporation of a nitrogen atom in the new constrained ring allowed us to develop SAR around the S2' binding pocket and ultimately resulted in analogues with low nanomolar potency for BACE1. In particular, optimization of the prime side substituent led to major improvements in potency by displacement of two conserved water molecules from a region near S2'. Further optimization of the pharmacokinetic properties of this fused pyrrolidine series, in conjunction with facile access to a rat pharmacodynamic model, led to identification of compound 43, which is an orally active, brain penetrant inhibitor that reduces Aβ(40) in the plasma, CSF, and cortex of rats in a dose-dependent manner.

Microsecond molecular dynamics simulation of Aβ42 and identification of a novel dual inhibitor of Aβ42 aggregation and BACE1 activity

“…In the past decades, many X-ray structures of the apo BACE1 and the BACE1-inhibitor complex have been deter-www.nature.com/aps Wang YY et al Acta Pharmacologica Sinica npg mined, which provide detailed information about the structure and functional analysis of BACE1 [11][12][13][14][15][16] . BACE1 is a membraneanchored aspartic protease containing three distinct domains: an N-terminal ectodomain, a single transmembrane domain, and a cytosolic C-terminus.…”

Conformational Restriction: An Effective Tactic in ‘Follow-On’-Based Drug Discovery

“…To further improve the potency of BACE1 inhibitors, structure-based evolution combined with conformational constraint strategy of these lead compounds 3, 5, 7, 9 and 11 was performed to facilitate access to the prime side of the BACE1 active site, which provided the discovery of the corresponding conformationally restricted analogues (such as 3-hydroxypyrrolidine 4 [16], imidazo[1,2-a]pyridine 6 [17], pyrrolidine 8 [18], bicyclic iminopyrimidinone 10 [19] and chiral cyclopropanes 12a-c [20,21]; Figure 1). …”

“…Conformational restriction: an effective tactic in 'follow-on'-based drug discovery Review fied as an orally active, brain penetrant molecule that can lower amyloid-β (Aβ)40 in the plasma, cerebrospinal fluid and cortex of rats in a dose-dependent manner (Figure 1) [19]. Furthermore, γ-secretase modulators have emerged as a potential disease-modifying treatment for AD.…”

“…Bis-azamacrocyclic compound AMD3100 (19) has been regarded as a highly effective antagonist of the chemokine (C-X-C motif) receptor type 4 (CXCR4). The two azamacrocyclic rings have shown to interact with aspartate residues on the receptor via electrostatic and hydrogen bonding interactions [27].…”

Critical analysis of the use of β-site amyloid precursor protein-cleaving enzyme 1 inhibitors in the treatment of Alzheimer's disease

“…Merck researchers have developed several lead compounds that were identified through screening of a million compounds from drug libraries, and these have produced a large number of molecules that potently inhibit BACE1 in vitro. [107][108][109][110][111] Trials of selected drugs in primate models have shown very promising potential, with near-complete inhibition of Aβ levels in the brain and CSF. 112,113 Compound MK-8931 has now progressed to Phase II clinical trials, and presentations at conferences suggest this is currently the most advanced BACE1 inhibitor in human trials.…”