4 research outputs found
Mass-spectrometric analysis of agonist-induced retinoic acid receptor γ conformational change
Discovery of Danoprevir (ITMN-191/R7227), a Highly Selective and Potent Inhibitor of Hepatitis C Virus (HCV) NS3/4A Protease
HCV serine protease NS3 represents
an attractive drug target because it is not only essential for viral
replication but also implicated in the viral evasion of the host immune
response pathway through direct cleavage of key proteins in the human
innate immune system. Through structure-based drug design and optimization,
macrocyclic peptidomimetic molecules bearing both a lipophilic P2
isoindoline carbamate and a P1/P1′ acylsulfonamide/acylsulfamide
carboxylic acid bioisostere were prepared that possessed subnanomolar
potency against the NS3 protease in a subgenomic replicon-based cellular
assay (Huh-7). Danoprevir (compound <b>49</b>) was selected
as the clinical development candidate for its favorable potency profile
across multiple HCV genotypes and key mutant strains and for its good
in vitro ADME profiles and in vivo target tissue (liver) exposures
across multiple animal species. X-ray crystallographic studies elucidated
several key features in the binding of danoprevir to HCV NS3 protease
and proved invaluable to our iterative structure-based design strategy