Abstract：
:HCV infection is considered a silent epidemic because most people infected do not develop acute symptoms. Instead, the disease progresses to a chronic state leading to cirrhosis and hepatocarcinoma. Novel therapies are needed to combat this major health threat. The HCV NS3 serine protease has been the target of continuous investigation because of its pivotal role in viral replication. Herein, we present the P1-P3 macrocyclization approach followed for identification of HCV NS3 inhibitors as potential backup candidates to our first generation drug candidate, Sch 503034 (1). Different P1-P3 linkers were investigated to identify novel macrocyclic scaffolds. SAR exploration of P3-caps in the macrocyclic cores allowed the identification of l-serine derived macrocycle 32 (Ki* = 3 nM, EC90 = 30 nM) and allo-threonine derived macrocycle 36 (Ki* = 3 nM, EC90 = 30 nM) as potent HCV NS3 protease inhibitors.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Velázquez F,Venkatraman S,Blackman M,Pinto P,Bogen S,Sannigrahi M,Chen K,Pichardo J,Hart A,Tong X,Girijavallabhan V,Njoroge FGdoi
10.1021/jm801201usubject
Has Abstractpub_date
2009-02-12 00:00:00pages
700-8issue
3eissn
0022-2623issn
1520-4804pii
10.1021/jm801201ujournal_volume
52pub_type
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