Incorporation of fluorine atom(s) is a common tactic in medicinal chemistry to improve potency and to address ADME issues. Strategic use of fluorine within the gamma-secretase modulator (GSM) program afforded increased potency, and improved pharmacokinetic properties by blocking metabolic soft spots guided by Met ID studies. Gamma-secretase modulators (GSMs) have emerged as a potential disease modifying treatment for Alzheimer's disease, but as an intra-membrane cleaving aspartyl protease, gamma-secretase represents a challenging drug target leading to compounds that often push the boundaries for acceptable CNS physicochemical property space. An analysis of the Pfizer MDR efflux ratio data set demonstrated that an increase in molecular weight due to introduction of one or more fluorine atoms has negligible impact on P-gp mediated efflux. Application of these concepts to the GSM program has allowed alignment of potency and ADME while maintaining excellent brain penetration.

Gamma-secretase modulators: Aligning potency, clearance, and brain penetration through strategic use of fluorine

245th National Meeting (2013)

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