title: Structure-activity relationship study on a novel series of cyclopentane-containing macrocyclic inhibitors of the hepatitis C virus NS3/4A protease leading to the discovery of TMC435350.
abstract: SAR analysis performed with a limited set of cyclopentane-containing macrocycles led to the identification of N-[17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo [13.3.0.0(4,6)]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (TMC435350, 32c) as a potent inhibitor of HCV NS3/4A protease (K(i)=0.36nM) and viral replication (replicon EC(50)=7.8nM). TMC435350 also displayed low in vitro clearance and high permeability, which were confirmed by in vivo pharmacokinetic studies. TMC435350 is currently being evaluated in the clinics.
authors.affiliation: Tibotec BVBA, Gen. De Wittelaan L11 B3, B-2800 Mechelen, Belgium.
authors.forename: Pierre
authors.initials: P
authors.lastname: Raboisson
authors.forename: Herman
authors.initials: H
authors.lastname: de Kock
authors.forename: Asa
authors.initials: A
authors.lastname: Rosenquist
authors.forename: Magnus
authors.initials: M
authors.lastname: Nilsson
authors.forename: Lourdes
authors.initials: L
authors.lastname: Salvador-Oden
authors.forename: Tse-I
authors.initials: TI
authors.lastname: Lin
authors.forename: Natalie
authors.initials: N
authors.lastname: Roue
authors.forename: Vladimir
authors.initials: V
authors.lastname: Ivanov
authors.forename: Horst
authors.initials: H
authors.lastname: Wähling
authors.forename: Kristina
authors.initials: K
authors.lastname: Wickström
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hamelink
authors.forename: Michael
authors.initials: M
authors.lastname: Edlund
authors.forename: Lotta
authors.initials: L
authors.lastname: Vrang
authors.forename: Sandrine
authors.initials: S
authors.lastname: Vendeville
authors.forename: Wim
authors.initials: W
authors.lastname: Van de Vreken
authors.forename: David
authors.initials: D
authors.lastname: McGowan
authors.forename: Abdellah
authors.initials: A
authors.lastname: Tahri
authors.forename: Lili
authors.initials: L
authors.lastname: Hu
authors.forename: Carlo
authors.initials: C
authors.lastname: Boutton
authors.forename: Oliver
authors.initials: O
authors.lastname: Lenz
authors.forename: Frederic
authors.initials: F
authors.lastname: Delouvroy
authors.forename: Geert
authors.initials: G
authors.lastname: Pille
authors.forename: Dominique
authors.initials: D
authors.lastname: Surleraux
authors.forename: Piet
authors.initials: P
authors.lastname: Wigerinck
authors.forename: Bertil
authors.initials: B
authors.lastname: Samuelsson
authors.forename: Kenneth
authors.initials: K
authors.lastname: Simmen
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002460:Cell Line; D003517:Cyclopentanes / Q000737:chemistry / Q000494:pharmacology*; D004285:Dogs; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology*; D006526:Hepatitis C / Q000188:drug therapy; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D047028:Macrocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000069616:Simeprevir; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014764:Viral Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D002352:Carrier Proteins; D003517:Cyclopentanes; D006575:Heterocyclic Compounds, 3-Ring; D047908:Intracellular Signaling Peptides and Proteins; D047028:Macrocyclic Compounds; D011480:Protease Inhibitors; D000069616:Simeprevir; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C455041:NS4A cofactor peptide, Hepatitis C virus