13 research outputs found
A Bibliography of Community Analyses for Libraries
published or submitted for publicatio
Some Limits to Subject Retrieval From a Large Published Index
191 p.Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 1979.U of I OnlyRestricted to the U of I community idenfinitely during batch ingest of legacy ETD
Identification and Preclinical Pharmacology of the γ-Secretase Modulator BMS-869780
Alzheimer’s disease is the most prevalent cause of dementia and is associated with accumulation of amyloid-β peptide (Aβ), particularly the 42-amino acid Aβ1-42, in the brain. Aβ1-42 levels can be decreased by γ-secretase modulators (GSM), which are small molecules that modulate γ-secretase, an enzyme essential for Aβ production. BMS-869780 is a potent GSM that decreased Aβ1-42 and Aβ1-40 and increased Aβ1-37 and Aβ1-38, without inhibiting overall levels of Aβ peptides or other APP processing intermediates. BMS-869780 also did not inhibit Notch processing by γ-secretase and lowered brain Aβ1-42 without evidence of Notch-related side effects in rats. Human pharmacokinetic (PK) parameters were predicted through allometric scaling of PK in rat, dog, and monkey and were combined with the rat pharmacodynamic (PD) parameters to predict the relationship between BMS-869780 dose, exposure and Aβ1-42 levels in human. Off-target and safety margins were then based on comparisons to the predicted exposure required for robust Aβ1-42 lowering. Because of insufficient safety predictions and the relatively high predicted human daily dose of 700 mg, further evaluation of BMS-869780 as a potential clinical candidate was discontinued. Nevertheless, BMS-869780 demonstrates the potential of the GSM approach for robust lowering of brain Aβ1-42 without Notch-related side effects
Acyl Guanidine Inhibitors of β‑Secretase (BACE-1): Optimization of a Micromolar Hit to a Nanomolar Lead via Iterative Solid- and Solution-Phase Library Synthesis
This report describes the discovery and optimization
of a BACE-1
inhibitor series containing an unusual acyl guanidine chemotype that
was originally synthesized as part of a 6041-membered solid-phase
library. The synthesis of multiple follow-up solid- and solution-phase
libraries facilitated the optimization of the original micromolar
hit into a single-digit nanomolar BACE-1 inhibitor in both radioligand
binding and cell-based functional assay formats. The X-ray structure
of representative inhibitors bound to BACE-1 revealed a number of
key ligand:protein interactions, including a hydrogen bond between
the side chain amide of flap residue Gln73 and the acyl guanidine
carbonyl group, and a cation−π interaction between Arg235
and the isothiazole 4-methoxyphenyl substituent. Following subcutaneous
administration in rats, an acyl guanidine inhibitor with single-digit
nanomolar activity in cells afforded good plasma exposures and a dose-dependent
reduction in plasma Aβ levels, but poor brain exposure was observed
(likely due to Pgp-mediated efflux), and significant reductions in
brain Aβ levels were not obtained