title: Inhibitors of the hepatitis C virus NS3 protease with basic amine functionality at the P3-amino acid N-terminus: discovery and optimization of a new series of P2-P4 macrocycles.
abstract: In a follow-up to our recent disclosure of P2-P4 macrocyclic inhibitors of the hepatitis C virus (HCV) NS3 protease (e.g., 1, Chart 1), we report a new but related compound series featuring a basic amine at the N-terminus of the P3-amino acid residue. Replacement of the electroneutral P3-amino acid capping group (which is a feature of almost all tripeptide-like inhibitors of NS3 reported to date) with a basic group is not only tolerated but can result in advantageous cell based potency. Optimization of this new class of P3-amine based inhibitors gave compounds such as 25 and 26 that combine excellent cell based activity with pharmacokinetic properties that are attractive for an antiviral targeting HCV.
authors.affiliation: IRBM (Merck Research Laboratories Rome), Via Pontina km 30,600, 00040 Pomezia, Rome, Italy. steven_harper@merck.com
authors.forename: Steven
authors.initials: S
authors.lastname: Harper
authors.forename: Marco
authors.initials: M
authors.lastname: Ferrara
authors.forename: Benedetta
authors.initials: B
authors.lastname: Crescenzi
authors.forename: Marco
authors.initials: M
authors.lastname: Pompei
authors.forename: Maria Cecilia
authors.initials: MC
authors.lastname: Palumbi
authors.forename: Jillian M
authors.initials: JM
authors.lastname: DiMuzio
authors.forename: Monica
authors.initials: M
authors.lastname: Donghi
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Fiore
authors.forename: Uwe
authors.initials: U
authors.lastname: Koch
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Liverton
authors.forename: Silvia
authors.initials: S
authors.lastname: Pesci
authors.forename: Alessia
authors.initials: A
authors.lastname: Petrocchi
authors.forename: Michael
authors.initials: M
authors.lastname: Rowley
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Summa
authors.forename: Cristina
authors.initials: C
authors.lastname: Gardelli
mesh_terms: D000588:Amines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D004285:Dogs; D055808:Drug Discovery; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000588:Amines; D000998:Antiviral Agents; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases