- Discovery of hepatitis C Virus NS3-4A protease inhibitors with improved barrier to resistance and favorable liver distribution
-
Given the emergence of resistance observed for the current clinical-stage hepatitis C virus (HCV) NS3 protease inhibitors, there is a need for new inhibitors with a higher barrier to resistance. We recently reported our rational approach to the discovery of macrocyclic acylsulfonamides as HCV protease inhibitors addressing potency against clinically relevant resistant variants. Using X-ray crystallography of HCV protease variant/inhibitor complexes, we shed light on the complex structural mechanisms by which the D168V and R155K residue mutations confer resistance to NS3 protease inhibitors. Here, we disclose SAR investigation and ADME/PK optimization leading to the identification of inhibitors with significantly improved potency against the key resistant variants and with increased liver partitioning.
- Moreau, Benoi?t,O'Meara, Jeff A.,Bordeleau, Josée,Garneau, Michel,Godbout, Cedrickx,Gorys, Vida,Leblanc, Mélissa,Villemure, Elisia,White, Peter W.,Llinàs-Brunet, Montse
-
supporting information
p. 1770 - 1776
(2014/04/03)
-
- ZnO nanoparticles-mediated regioselective synthesis of methyl-iV-alkylated 1,2,3-triazole-4-carboxylates
-
The 1,2,3-triazoles are versatile synthetic intermediates of many biologically active compounds, and their N-1 substituted analogues are potential pharmaceutically important derivatives. In this study, an efficient regioselective N-alkylation reaction of
- Prabakaran,Khan, Fazlur-Rahman Nawaz,Jin, Jong Sung
-
experimental part
p. 1101 - 1109
(2012/08/28)
-
- HEPATITIS C INHIBITOR COMPOUNDS
-
Compounds of Formula (I) wherein R1, R2, R3, R4 and R5 are defined herein, maintain good activity against NS3 proteases containing clinically relevant genotype 1a R155K and genotype 1b D168V resistance mutations. The compounds are useful as inhibitors of HCV NS3 protease for the treatment of hepatitis C viral infection.
- -
-
Page/Page column 49
(2011/06/23)
-
- HEPATITIS C INHIBITOR COMPOUNDS
-
Compounds of the invention, which are macrocyclic peptide analogs containing an acylsulfonamide moiety, maintain good activity against NS3 proteases containing clinically relevant resistance mutations for this class as represented by genotype 1 a R155K, genotype 1 b D168V and genotype 1 a D168V resistance mutations. The compounds of the invention are useful as inhibitors of HCV NS3 protease for the treatment of hepatitis C viral infection.
- -
-
Page/Page column 33
(2011/06/23)
-
- NOVEL HERBICIDES
-
Compounds of formula I: wherein R1, R2, R3, R4, m, R5, R6, n and Y are as defined in claim 1; or N-oxides, salts and optical isomers thereof. Furthermore, the present invention relates to processes for preparing compounds of formula (I), to herbicidal compositions comprising them and to methods of using them to control plants or to inhibit plant growth.
- -
-
Page/Page column 110
(2008/06/13)
-
- HERBICIDAL ISOXAZOLINE COMPOUNDS
-
Novel compounds of formula (I): wherein R1, R2, R3, R4, m, R5, R6, n and Y are as defined in claim 1; or N-oxides, salts and optical isomers thereof. Furthermore, the present invention relates to processes for preparing compounds of formula (I), to herbicidal compositions comprising them and to methods of using them to control plants or to inhibit plant growth.
- -
-
-
- 1,3-Dipolar Cycloadditions, 93. - The Astounding Reaction of Dimethyl 2,3-Dicyanofumarate with Diazomethane
-
The reaction with excess of diazomethane furnished methyl 4-cyano-1-methylpyrazole-5- and -3-carboxylate (2 and 3) as well as the three N-methyl-1,2,3-triazolecarboxylic esters 4-6.A mechanistic study revealed a poly-step sequence.The initial formation of the pyrazoline 8 proceeded normal.Base catalysis effected an equilibration of trans- and cis-2-pyrazoline, 8(*)12, followed by a fragmentation into methyl 4-cyano-3-pyrazolecarboxylate (26) and methyl cyanoformate (32); a 4H-pyrazole is supposed to be the key intermediate.The final products mentioned above emerged from further reaction of 26 and 32 with diazomethane.
- Huisgen, Rolf,Mitra, Abhijit,Moran, Joaquin Rodriguez
-
p. 159 - 170
(2007/10/02)
-
- THE ASTOUNDING REACTION OF DIAZOMETHANE WITH DIMETHYL 2,3-DICYANOFUMARATE
-
The title reaction afforded the pyrazole derivatives 3 and 4 as well as the N-methyl-1,2,3-triazolecarboxylic esters 5 - 7.The poly-step sequence was clarified; the key intermediates are the 1-pyrazoline 18, the 2-pyrazoline 2, the 4H-pyrazole 12, the pyrazole 22, and methyl cyanoformate.
- Huisgen, Rolf,Mitra, Abhijit,Moran, Joaquin Rodriguez
-
p. 2429 - 2436
(2007/10/02)
-