title: Discovery of daclatasvir, a pan-genotypic hepatitis C virus NS5A replication complex inhibitor with potent clinical effect.
abstract: The discovery and development of the first-in-class hepatitis C virus (HCV) NS5A replication complex inhibitor daclatasvir (6) provides a compelling example of the power of phenotypic screening to identify leads engaging novel targets in mechanistically unique ways. HCV NS5A replication complex inhibitors are pan-genotypic in spectrum, and this mechanistic class provides the most potent HCV inhibitors in vitro that have been described to date. Clinical trials with 6 demonstrated a potent effect on reducing plasma viral load and, in combination with mechanistically orthogonal HCV inhibitors, established the ability to cure even the most difficult infections without the need for immune stimulation. In this Drug Annotation, we describe the discovery of the original high-throughput screening lead 7 and the chemical conundrum and challenges resolved in optimizing to 6 as a clinical candidate and finally we summarize the results of select clinical studies.
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Makonen
authors.initials: M
authors.lastname: Belema
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Meanwell
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D002219:Carbamates; D002986:Clinical Trials as Topic; D024882:Drug Resistance, Viral; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011759:Pyrrolidines; D013329:Structure-Activity Relationship; D014633:Valine / Q000031:analogs & derivatives; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D011759:Pyrrolidines; D014633:Valine; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C549273:daclatasvir