Journal Article
Discovery of a Potent and Orally Bioavailable Cyclophilin Inhibitor Derived from the Sanglifehrin Macrocycle
Mackman, RL; Cannizzaro, C; Chin, G; Chiva, JYC; Dunbar, NA; Fliri, H; Highton, AJ; Hui, Hon; Ji, M; Jin, H; Karki, K; Steadman, VA; Keats, AJ; Lazarides, L; Lee, Y; Liclican, A; Mish, M; Murray, B; Pettit, SB; Pyun, P; Sangi, M; Santos, Rex; Dean, DK; Sanvoisin, J; Schmitz, Uli; Schrier, A; Siegel, D; Sperandio, D; Stepan, G; Tian, Y; Watt, GM; Yang, Hai; Schultz, BE; Jansa, P; Poullennec, KG; Appleby, T; Austin, C; Blakemore, CA; Cai, R; ,
Journal of Medicinal Chemistry
ISSN: 0022-2623
EISSN: 1520-4804
AMER CHEMICAL SOC
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-d = 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.
1 (7 bromo quinolin 2 yl) ethylamine hydrochloride; 10 isopropyl 2,7 dimethylspiro[11 oxa 3,8 diaza 1(2,7) quinolina 5(3,1) pyridazinacyclopentadecaphanene 13,5' [1,3]dioxan] 14 ene 4,6,9,12 tetraone; 10 isopropyl 2,7,13,13 tetramethyl 5 1,5 2,5 3,5 4,5 5,5 6 hexahydro 11 oxa 3,8 diaza 1( 2,7) quinolina 5(3,1) pyridazinacyclopentadecahan 14 ene 4,6,9,12 tetraone; 2,2 dimethyl 5 vinyl 1,3 dioxane 5 carboxylic acid; 2,2,2 trichloroethyl 1 [(1 hydroxy 3 methylbutanoyl) levo alanyl]hexahydropyradazine 3 carboxylate; 4 methoxy 1 vinylcyclohexane 1 carboxylic acid; 4 vinyltetrahydro 2h thiopyran 4 carboxylic acid 1,1 dioxide; 4 [2 [1 [(tert butoxycarbonyl)amino]ethyl]quinolin 7 yl]vinyl] tetrahydro 2h pyran 4 carboxylic acid; 4 [6 (1 hydroxyethyl)isoquinolin 3 yl) 2,2 dimethylbut 3 enoic; 4 [6 [1 [(tert butoxycarbonyl)amino]ethy]isoquinolin 3 yl] 2,2 dimethylbut 3 enoic acid; 5 vinyl 1,3 dioxane 5 carboxylic acid; 6 (nitromethylene) 1,4 dioxepane; 6 vinyl 1,4 dioxepane 6 carboxylic acid; antivirus agent; cyclophilin inhibitor; ethyl 1 [2 [2 [1 [(tert butoxycarbonyl)amino]ethyl]quinolin 7 yl]vinyl] 4 oxocyclohexane 1 carboxylate; ethyl 5 acetyl 2,2 dimethyl 1,3 dioxane 5 carboxylate; macrocyclic compound; methyl 1 [2 [2 [1 [(tert butocycarbonyl)aminoethyl]quolin 7 yl]vinyl] 4 methoxy cyclohexane 1 carboxylate; methyl 2,2 dimethyl 4 (4,4,5,5 tetramethyl 1,3,2 dioxaborolan 2 yl)but 3 enoate; methyl 4 (1 hydroxyethyl)tetrahydro 2h thiopyran 4 carboxylate 1,1 dioxide; methyl 4 vinyltetrahydro 2h pyran 4 carboxylate; methyl 4 [2 (1 aminoethyl)quinolin 7 yl] 2,2 dimethylbut 3 enoate; n [1 (3 chloroisoquinolin 6 yl)ethyl] 2 methylpropane 2 sulfinamide; n [1 (7 bromoquinolin 2 yl)ethyl] 1 [(2 hydroxy 3 methylbutanoyl) levo alanyl]hexahydropyridazine 3 carboxamide; n [1 (7 bromoquinolin 2 yl)ethy] 2 methylpropane 2 sulfinamide; sanglifehrin A; tert butyl [1 (3 chloroisoquinolin 6 yl)ethyl]carbamate; tert butyl [1 (7 bromoquinolin 2 yl)ethyl]carbamate; unclassified drug; unindexed drug; antivirus agent; cyclophilin; enzyme inhibitor; lactone; sanglifehrin A; spiro compound; animal experiment; antiviral activity; Article; controlled study; drug bioavailability; drug potency; drug structure; drug synthesis; enzyme inhibition; hydrogen bond; nonhuman; rat; bioavailability; cell line; chemistry; drug design; drug effect; Hepacivirus; molecular model; oral drug administration; protein conformation; Administration, Oral; Antiviral Agents; Biological Availability; Cell Line; Cyclophilins; Drug Design; Enzyme Inhibitors; Hepacivirus; Lactones; Models, Molecular; Protein Conformation; Spiro Compounds