P2‐375: Efficacy of the novel γ‐secretase inhibitor, PF‐3084014, in reducing Aβ in brain, CSF, and plasma in guinea pigs and Tg2576 mice

Reducing Aβ load and tau phosphorylation: Emerging perspective for treating Alzheimer's disease

“…Data from animal studies show a decrease in Aβ levels in plasma, CSF and brain, without any rebound effect on plasma Aβ (Wood et al, 2008;Niva et al, 2013). In addition to this, PF-3084014 also promoted dose-dependent decrease in plasma Aβ concentrations in small phase I study conducted in healthy volunteers although, effects on CSF concentrations were small (Soares et al, 2009).…”

Challenges in Designing Therapeutic Agents for Treating Alzheimer’s Disease-from Serendipity to Rationality

“…At the 2011 AAIC, Bristol-Myers Squibb Company (BMY) announced the results of a Phase-II study evaluating the safety and tolerability of the investigational oral GSI avagacestat (20, in patients with mild-to-moderate AD [148,176,177]. PF-3084014 (23) is a novel tetralin imidazole GSI with 10-100 fold selectivity for APP compared with Notch [181]. Later the trials for both compounds were halted due to liver toxicity [176][177][178][179][180].…”

REVIEW: γ‐Secretase Inhibitors for the Treatment of Alzheimer's Disease: The Current State

“…PF‐3084014 is a potent, Notch‐sparing, γ‐secretase inhibitor in development at Pfizer. In a cell‐free assay, PF‐3084014 appears to be a potent, noncompetitive but reversible inhibitor of human γ‐secretase activity with an IC50 of 6.2 nM [45]. In a whole‐cell assay, PF‐3084014 displays an IC50 of 1.3 nM.…”

“…Benzodiazepine analog LY‐411575 and benzolactam semagacestat (LY‐450139), developed at Eli Lilly, are highly potent γ‐secretase inhibitors that have been tested extensively in vivo [41,42]. At least five other γ‐secretase inhibitors reached the clinic, and most of the information on these other compounds is derived from conference communications: MK‐0752 [43], BMS‐708163 [44], PF‐3084014 (abandoned) [45], and GSI‐953 (begacestat) [46], and E2012 [40] (Table 1). Some γ‐secretase inhibitors appear to spare Notch cleavage in vitro and are relatively well tolerated in man.…”