The Discovery of Potent Nonstructural Protein 5A (NS5A) Inhibitors with a Unique Resistance Profile—Part 1

Abstract

Nonstructural protein 5A (NS5A) represents a novel target for the treatment of hepatitis C virus (HCV). Daclatasvir, recently reported by Bristol-Myers-Squibb, is a potent NS5A inhibitor currently under investigation in phase 3 clinical trials. While the performance of daclatasvir has been impressive, the emergence of resistance could prove problematic and as such, improved analogues are being sought. By varying the biphenyl-imidazole unit of daclatasvir, novel inhibitors of HCV NS5A were identified with an improved resistance profile against mutant strains of the virus while retaining the picomolar potency of daclatasvir. One compound in particular, methyl ((S)-1-((S)-2-(4-(4-(6-(2-((S)-1-((methoxycarbonyl)-L-valyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)quinoxalin-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (17), exhibited very promising activity and showed good absorption and a long predicted human pharmacokinetic half-life. This compound represents a promising lead that warrants further evaluation.

Bioactivity Focus of α-Cyano-4-hydroxycinnamic acid (CHCA) Leads to Effective Multifunctional Aldose Reductase Inhibitors

“…Epalrestat was used as a positive reference. ALR2 inhibition was determined spectrophotometrically according to the procedure described previously 52 .…”

Site-selective Suzuki–Miyaura coupling of heteroaryl halides – understanding the trends for pharmaceutically important classes

“…By contrast, 6-bromo-2-chloroquinoxaline ( 43 ) 61 and 6-bromo-2-chloro-8-fluoroquinazoline ( 45 ) 62 both react in SMC reactions first at the chlorides at C2 in preference to the bromides at C6 ( Scheme 9 ).…”

Chemodivergence between Electrophiles in Cross‐Coupling Reactions

“… Substrates that have been shown to undergo selective cross‐coupling at the indicated chloride, despite the presence of a weaker C−Br or C−I bond [77–84] …”

“…Substratest hat havebeen shown to undergo selective crosscoupling at the indicated chloride, despite the presence of aw eaker CÀBr or CÀIbond. [77][78][79][80][81][82][83][84] Scheme30. Pd-catalyzed amination of 2-chloro-5-iodopyridine in the presence of ab isimidazol-2-ylidene ligand favorsreaction of CÀCl over CÀI.…”