Objective

Cyclophilins (Cyps) are a family of peptidyl-prolyl isomerases involved in a range of biological processes and implicated in a variety of diseases.  Our endeavour was to identify a synthetic, orally bioavailable, non-immunosuppressive small molecule Cyp inhibitor with potent anti-Hepatitis C virus (HCV) activity that could serve as part of an all oral antiviral combination therapy. 

Our drug discovery approach was focussed on the structural simplification of the known Cyp inhibitor natural product Sanglifehrin A. Our efforts resulted in an initial simplified lead 2 which was further optimized using structure based design to 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<10 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.