title: Discovery of danoprevir (ITMN-191/R7227), a highly selective and potent inhibitor of hepatitis C virus (HCV) NS3/4A protease.
abstract: HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimization, macrocyclic peptidomimetic molecules bearing both a lipophilic P2 isoindoline carbamate and a P1/P1' acylsulfonamide/acylsulfamide carboxylic acid bioisostere were prepared that possessed subnanomolar potency against the NS3 protease in a subgenomic replicon-based cellular assay (Huh-7). Danoprevir (compound 49) was selected as the clinical development candidate for its favorable potency profile across multiple HCV genotypes and key mutant strains and for its good in vitro ADME profiles and in vivo target tissue (liver) exposures across multiple animal species. X-ray crystallographic studies elucidated several key features in the binding of danoprevir to HCV NS3 protease and proved invaluable to our iterative structure-based design strategy.
authors.affiliation: Array BioPharma , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Yutong
authors.initials: Y
authors.lastname: Jiang
authors.forename: Steven W
authors.initials: SW
authors.lastname: Andrews
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Condroski
authors.forename: Brad
authors.initials: B
authors.lastname: Buckman
authors.forename: Vlad
authors.initials: V
authors.lastname: Serebryany
authors.forename: Steve
authors.initials: S
authors.lastname: Wenglowsky
authors.forename: April L
authors.initials: AL
authors.lastname: Kennedy
authors.forename: Machender R
authors.initials: MR
authors.lastname: Madduru
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.forename: Michael
authors.initials: M
authors.lastname: Lyon
authors.forename: George A
authors.initials: GA
authors.lastname: Doherty
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Woodard
authors.forename: Christine
authors.initials: C
authors.lastname: Lemieux
authors.forename: Mary
authors.initials: M
authors.lastname: Geck Do
authors.forename: Hailong
authors.initials: H
authors.lastname: Zhang
authors.forename: Joshua
authors.initials: J
authors.lastname: Ballard
authors.forename: Guy
authors.initials: G
authors.lastname: Vigers
authors.forename: Barbra J
authors.initials: BJ
authors.lastname: Brandhuber
authors.forename: Peter
authors.initials: P
authors.lastname: Stengel
authors.forename: John A
authors.initials: JA
authors.lastname: Josey
authors.forename: Leonid
authors.initials: L
authors.lastname: Beigelman
authors.forename: Lawrence
authors.initials: L
authors.lastname: Blatt
authors.forename: Scott D
authors.initials: SD
authors.lastname: Seiwert
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D018360:Crystallography, X-Ray; D003521:Cyclopropanes; D004285:Dogs; D055808:Drug Discovery; D054833:Isoindoles; D007769:Lactams / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D047029:Lactams, Macrocyclic; D008252:Macaca fascicularis; D015394:Molecular Structure; D011392:Proline / Q000031:analogs & derivatives; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D003521:Cyclopropanes; D054833:Isoindoles; D007769:Lactams; D047029:Lactams, Macrocyclic; D011392:Proline; D011480:Protease Inhibitors; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C080106:NS4A protein, flavivirus; C553752:danoprevir