Discovery of Clinical Candidate PF-06648671: A Potent γ-Secretase Modulator for the Treatment of Alzheimer’s Disease
Martin Pettersson, Douglas S. Johnson, John M. Humphrey, Christopher W. am Ende, Todd W. Butler, Peter H. Dorff, Ivan V. Efremov, Edelweiss Evrard, Michael Green, Christopher J. Helal, Gregory W. Kauffman, Patrick B. Mullins, Thayalan Navaratnam, Christopher J. O’Donnell, Theresa J. O’Sullivan, Nandini C. Patel, Antonia F. Stepan, Cory M. Stiff, Chakrapani Subramanyam, Patrick E. Trapa · Journal of Medicinal Chemistry · 2024
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 IC 50 = 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).