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.
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.
Raboisson
Pierre
P
Tibotec BVBA, Gen. De Wittelaan L11 B3, B-2800 Mechelen, Belgium.
de Kock
Herman
H
Rosenquist
Asa
A
Nilsson
Magnus
M
Salvador-Oden
Lourdes
L
Lin
Tse-I
TI
Roue
Natalie
N
Ivanov
Vladimir
V
Wähling
Horst
H
Wickström
Kristina
K
Hamelink
Elizabeth
E
Edlund
Michael
M
Vrang
Lotta
L
Vendeville
Sandrine
S
Van de Vreken
Wim
W
McGowan
David
D
Tahri
Abdellah
A
Hu
Lili
L
Boutton
Carlo
C
Lenz
Oliver
O
Delouvroy
Frederic
F
Pille
Geert
G
Surleraux
Dominique
D
Wigerinck
Piet
P
Samuelsson
Bertil
B
Simmen
Kenneth
K
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
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