Discovery of novel potent and selective dipeptide hepatitis C virus NS3/4A serine protease inhibitors.
Starting from the previously reported HCV NS3/4A protease inhibitor BILN 2061, we have used a fast-follower approach to identify a novel series of HCV NS3/4A protease inhibitors in which (i) the P3 amino moiety and its capping group have been truncated, (ii) a sulfonamide is introduced in the P1 cyclopropyl amino acid, (iii) the position 8 of the quinoline is substituted with a methyl or halo group, and (iv) the ring size of the macrocycle has been reduced to 14 atoms. SAR analysis performed with a limited set of compounds led to the identification of N-{17-[8-chloro-2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy]-2,14-dioxo-3,15-diazatricyclo [13.3.0.0 [Bartenschlager, R.; Lohmann, V. J. Gen. Virol. 2000, 81, 1631; Vincent Soriano, Antonio Madejon, Eugenia Vispo, Pablo Labarga, Javier Garcia-Samaniego, Luz Martin-Carbonero, Julie Sheldon, Marcelle Bottecchia, Paula Tuma, Pablo Barreiro Expert Opin. Emerg. Drugs, 2008, 13, 1-19]]octadec-7-ene-4-carbonyl}(1-methylcyclopropyl)(1-methylcyclopropyl)sulfonamide 19l an extremely potent (K(i)=0.20 nM, EC(50)=3.7 nM), selective, and orally bioavailable dipeptide NS3/4A protease inhibitor, which has features attractive for further preclinical development.
Raboisson
Pierre
P
Tibotec BVBA, Gen. De Wittelaan L11 B3, B-2800 Mechelen, Belgium. praboiss@tibbe.jnj.com
Lin
Tse-I
TI
Kock
Herman de
Hd
Vendeville
Sandrine
S
Vreken
Wim Van de
WV
McGowan
David
D
Tahri
Abdellah
A
Hu
Lili
L
Lenz
Oliver
O
Delouvroy
Frederic
F
Surleraux
Dominique
D
Wigerinck
Piet
P
Nilsson
Magnus
M
Rosenquist
Sa
S
Samuelsson
Bertil
B
Simmen
Kenneth
K
D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques; D004285:Dogs; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D047028:Macrocyclic Compounds / Q000494:pharmacology*; D015394:Molecular Structure; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000998:Antiviral Agents; D002219:Carbamates; D047028:Macrocyclic Compounds; D011804:Quinolines; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; D013844:Thiazoles; D017361:Viral Nonstructural Proteins; C479555:BILN 2061; C532104:N-(17-(8-chloro-2-((4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy)-2,14-dioxo-3,15-diazatricyclo(13.3.0.0)-octadec-7-ene-4-carbonyl)-1-methylcyclopropyl)-(1-methylcyclopropyl)sulfonamide; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C093542:NS4 protein, hepatitis C virus