Alzheimer’s disease is a devastating neurodegenerative disorder where formation and deposition of neurotoxic oligomers of amyloid β42 (Aβ42) is believed to play a pivotal role. Aβ42 is derived from the amyloid precursor protein (APP) via sequential processing by the β-secretase (BACE) and γ-secretase enzymes. Over the past decade, γ-secretase modulators (GSM) have emerged as promising therapeutic agents for selectively reducing brain levels of the neurotoxic Aβ species without inhibiting γ-secretase cleavage of other critical substrates such as the Notch receptor. However, γ-secretase is an intramembrane aspartyl protease, and designing potent modulators within good physicochemical property space to ensure an adequate safety profile for clinical development has proven to be particularly challenging.<br/><br/>This presentation will describe the medicinal chemistry design strategies that resulted in clinical candidate PF-06648671. Successful lead optimization was enabled by ligand-based design tactics such as development of a pharmacophore model, introduction of rigid structural motifs to lock the molecule into its putative bioactive conformation, and design of a novel, heterocyclic core with increased polarity. Efficient use of parallel medicinal chemistry facilitated rapid evaluation of chemical space. Ultimately, we were able to achieve an optimal balance of in vitro potency and ADME parameters to afford the clinical candidate PF-06648671 with excellent brain penetration and robust in vivo efficacy. This presentation will also highlight human pharmacokinetics data and reduction of Aβ42 in human cerebrospinal fluid.

Discovery of clinical candidate PF-06648671: A potent, highly brain penetrant gamma secretase modulator for the treatment of Alzheimer’s disease

253rd National Meeting (2017)

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