title: Synthesis and SAR of potent inhibitors of the Hepatitis C virus NS3/4A protease: exploration of P2 quinazoline substituents.
abstract: Novel NS3/4A protease inhibitors comprising quinazoline derivatives as P2 substituent were synthesized. High potency inhibitors displaying advantageous PK properties have been obtained through the optimization of quinazoline P2 substituents in three series exhibiting macrocyclic P2 cyclopentane dicarboxylic acid and P2 proline urea motifs. For the quinazoline moiety it was found that 8-methyl substitution in the P2 cyclopentane dicarboxylic acid series improved on the metabolic stability in human liver microsomes. By comparison, the proline urea series displayed advantageous Caco-2 permeability over the cyclopentane series. Pharmacokinetic properties in vivo were assessed in rat on selected compounds, where excellent exposure and liver-to-plasma ratios were demonstrated for a member of the 14-membered quinazoline substituted P2 proline urea series.
authors.affiliation: Medivir AB, PO Box 1086, SE-141 22 Huddinge, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Nilsson
authors.forename: Anna Karin
authors.initials: AK
authors.lastname: Belfrage
authors.forename: Stefan
authors.initials: S
authors.lastname: Lindström
authors.forename: Horst
authors.initials: H
authors.lastname: Wähling
authors.forename: Charlotta
authors.initials: C
authors.lastname: Lindquist
authors.forename: Susana
authors.initials: S
authors.lastname: Ayesa
authors.forename: Pia
authors.initials: P
authors.lastname: Kahnberg
authors.forename: Mikael
authors.initials: M
authors.lastname: Pelcman
authors.forename: Kurt
authors.initials: K
authors.lastname: Benkestock
authors.forename: Tatiana
authors.initials: T
authors.lastname: Agback
authors.forename: Lotta
authors.initials: L
authors.lastname: Vrang
authors.forename: Ylva
authors.initials: Y
authors.lastname: Terelius
authors.forename: Kristina
authors.initials: K
authors.lastname: Wikström
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hamelink
authors.forename: Christina
authors.initials: C
authors.lastname: Rydergård
authors.forename: Michael
authors.initials: M
authors.lastname: Edlund
authors.forename: Anders
authors.initials: A
authors.lastname: Eneroth
authors.forename: Pierre
authors.initials: P
authors.lastname: Raboisson
authors.forename: Tse-I
authors.initials: TI
authors.lastname: Lin
authors.forename: Herman
authors.initials: H
authors.lastname: de Kock
authors.forename: Piet
authors.initials: P
authors.lastname: Wigerinck
authors.forename: Kenneth
authors.initials: K
authors.lastname: Simmen
authors.forename: Bertil
authors.initials: B
authors.lastname: Samuelsson
authors.forename: Sa
authors.initials: S
authors.lastname: Rosenquist
mesh_terms: D019540:Area Under Curve; D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D016174:Hepacivirus / Q000201:enzymology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008862:Microsomes, Liver / Q000378:metabolism; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; 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; D047908:Intracellular Signaling Peptides and Proteins; D011480:Protease Inhibitors; D011799:Quinazolines; 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