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

Abstract

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 ( K = 5 nM), potent anti-HCV 2a activity (EC = 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.

Solution Conformations Explain the Chameleonic Behaviour of Macrocyclic Drugs

“…Their semi‐rigidity may also reduce the entropic cost for entering a cell membrane, while also providing potent target binding. Recently, both intramolecular hydrogen bonds and NH‐π interactions have been used in the design of orally administered and cell permeable drug candidates. Although such examples are still rare, they constitute the first step towards the wider incorporation of molecular chameleonicity in the design of chemical probes and drugs.…”

Drug Syntheses Beyond the Rule of 5

“…Figure ) illustrates how the target bound structure can be used to solve one of the most demanding issues for bRo5 drugs, that is, optimisation of pharmacokinetics to allow oral administration. The recent reports of how the structure of the complex between sanglifehrin A and cyclophilin A was used to develop a candidate drug for treatment of HCV infections provides yet another example of the power of incorporating structural information in bRo5 drug discovery . This work reports the use of rational structure‐based design to develop a much simplified analogue of a complex natural product so that it displays increased target selectivity and also high oral bioavailability.…”

Application of Chiral Sulfinamides into Formation and Reduction of Sulfinylketimines to Obtain Valuable α‐Chiral Primary Amines

“…Mackman et al synthesized sanglifehrin macrocycle derivatives as cyclophilin inhibitors. [71] Two building blocks were synthesized by the first condensation of (R)-tert-butylsulfinamide onto a ketone and then reduction of the sulfinylketimine using Yus conditions [42] (Scheme 63).…”