title: Potent nonimmunosuppressive cyclophilin inhibitors with improved pharmaceutical properties and decreased transporter inhibition.
abstract: Nonimmunosuppressive cyclophilin inhibitors have demonstrated efficacy for the treatment of hepatitis C infection (HCV). However, alisporivir, cyclosporin A, and most other cyclosporins are potent inhibitors of OATP1B1, MRP2, MDR1, and other important drug transporters. Reduction of the side chain hydrophobicity of the P4 residue preserves cyclophilin binding and antiviral potency while decreasing transporter inhibition. Representative inhibitor 33 (NIM258) is a less potent transporter inhibitor relative to previously described cyclosporins, retains anti-HCV activity in cell culture, and has an acceptable pharmacokinetic profile in rats and dogs. An X-ray structure of 33 bound to rat cyclophilin D is reported.
authors.affiliation: Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Jiping
authors.initials: J
authors.lastname: Fu
authors.forename: Meiliana
authors.initials: M
authors.lastname: Tjandra
authors.forename: Christopher
authors.initials: C
authors.lastname: Becker
authors.forename: Dallas
authors.initials: D
authors.lastname: Bednarczyk
authors.forename: Michael
authors.initials: M
authors.lastname: Capparelli
authors.forename: Robert
authors.initials: R
authors.lastname: Elling
authors.forename: Imad
authors.initials: I
authors.lastname: Hanna
authors.forename: Roger
authors.initials: R
authors.lastname: Fujimoto
authors.forename: Markus
authors.initials: M
authors.lastname: Furegati
authors.forename: Subramanian
authors.initials: S
authors.lastname: Karur
authors.forename: Theresa
authors.initials: T
authors.lastname: Kasprzyk
authors.forename: Mark
authors.initials: M
authors.lastname: Knapp
authors.forename: Kwan
authors.initials: K
authors.lastname: Leung
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Li
authors.forename: Peichao
authors.initials: P
authors.lastname: Lu
authors.forename: Wosenu
authors.initials: W
authors.lastname: Mergo
authors.forename: Charlotte
authors.initials: C
authors.lastname: Miault
authors.forename: Simon
authors.initials: S
authors.lastname: Ng
authors.forename: David
authors.initials: D
authors.lastname: Parker
authors.forename: Yunshan
authors.initials: Y
authors.lastname: Peng
authors.forename: Silvio
authors.initials: S
authors.lastname: Roggo
authors.forename: Alexey
authors.initials: A
authors.lastname: Rivkin
authors.forename: Robert L
authors.initials: RL
authors.lastname: Simmons
authors.forename: Michael
authors.initials: M
authors.lastname: Wang
authors.forename: Brigitte
authors.initials: B
authors.lastname: Wiedmann
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Weiss
authors.forename: Linda
authors.initials: L
authors.lastname: Xiao
authors.forename: Lili
authors.initials: L
authors.lastname: Xie
authors.forename: Wenjian
authors.initials: W
authors.lastname: Xu
authors.forename: Aregahegn
authors.initials: A
authors.lastname: Yifru
authors.forename: Shengtian
authors.initials: S
authors.lastname: Yang
authors.forename: Bo
authors.initials: B
authors.lastname: Zhou
authors.forename: Zachary K
authors.initials: ZK
authors.lastname: Sweeney
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D018360:Crystallography, X-Ray; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D016572:Cyclosporine / Q000737:chemistry / Q000494:pharmacology; D003524:Cyclosporins / Q000737:chemistry / Q000494:pharmacology*; D004285:Dogs; D016174:Hepacivirus / Q000187:drug effects; D006526:Hepatitis C / Q000188:drug therapy; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology; D027381:Liver-Specific Organic Anion Transporter 1; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors*; D051381:Rats; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins; D016572:Cyclosporine; D003524:Cyclosporins; D007166:Immunosuppressive Agents; D027381:Liver-Specific Organic Anion Transporter 1; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; C000597474:3-(N-methylalanyl)-4-(4-((tert-butyldiphenylsilyl)oxy)-3-methyl-2-(methylamino)butanoic acid)cyclosporin A; C000715087:ABCC2 protein, human; C503999:SLCO1B1 protein, human; C499715:alisporivir