Discovery of Clinical Candidate PF-06648671: A Potent γ‑Secretase Modulator for the Treatment of Alzheimer’s Disease

Herein, we describe the design and synthesis of γ-secretase
modulator (GSM) clinical candidate PF-06648671 (22) for
the treatment of Alzheimer’s disease. A key component of the
design involved a 2,5-cis-tetrahydrofuran (THF) linker
to impart conformational rigidity and lock the compound into a putative
bioactive conformation. This effort was guided using a pharmacophore
model since crystallographic information was not available for the
membrane-bound γ-secretase protein complex at the time of this
work. PF-06648671 achieved excellent alignment of whole cell in vitro
potency (Aβ42 IC50 = 9.8 nM) and absorption, distribution,
metabolism, and excretion (ADME) parameters. This resulted in favorable
in vivo pharmacokinetic (PK) profile in preclinical species, and PF-06648671
achieved a human PK profile suitable for once-a-day dosing. Furthermore,
PF-06648671 was found to have favorable brain availability in rodent,
which translated into excellent central exposure in human and robust
reduction of amyloid β (Aβ) 42 in cerebrospinal fluid
(CSF).