Discovery of a Potent and Orally Bioavailable Cyclophilin Inhibitor Derived from the Sanglifehrin Macrocycle

Cyclophilins are a family of peptidyl-prolyl
isomerases that are
implicated in a wide range of diseases including hepatitis C. Our
aim was to discover through total synthesis an orally bioavailable,
non-immunosuppressive cyclophilin (Cyp) inhibitor with potent anti-hepatitis
C virus (HCV) activity that could serve as part of an all oral antiviral
combination therapy. An initial lead 2 derived from the
sanglifehrin A macrocycle was optimized using structure based design
to produce a potent and orally bioavailable inhibitor 3. The macrocycle ring size was reduced by one atom, and an internal
hydrogen bond drove improved permeability and drug-like properties. 3 demonstrates potent Cyp inhibition (Kd = 5 nM), potent anti-HCV 2a activity (EC50 = 98
nM), and high oral bioavailability in rat (100%) and dog (55%). The
synthetic accessibility and properties of 3 support its
potential as an anti-HCV agent and for interrogating the role of Cyp
inhibition in a variety of diseases.