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

• Published in: Journal of medicinal chemistry 2009-08, Vol.52 (15), p.4820-4837
• Main Authors: Harper, Steven, Ferrara, Marco, Crescenzi, Benedetta, Pompei, Marco, Palumbi, Maria Cecilia, DiMuzio, Jillian M, Donghi, Monica, Fiore, Fabrizio, Koch, Uwe, Liverton, Nigel J, Pesci, Silvia, Petrocchi, Alessia, Rowley, Michael, Summa, Vincenzo, Gardelli, Cristina
• Format: Article
• Language: English
• Subjects: Amines - chemical synthesis; Amines - pharmacokinetics; Amines - pharmacology; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - pharmacokinetics; Antiviral Agents - pharmacology; Biological and medical sciences; Dogs; Drug Discovery; Male; Medical sciences; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Viral Nonstructural Proteins - antagonists & inhibitors
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm900372w

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.