A Concise Synthesis of the HCV Protease Inhibitor BILN.

Ciluprevir, also known as BILN 2061, is a potent and selective HCV NS3 protease inhibitor with proven antiviral effect in humans. In vitro sensitivity studies with BILN 2061 showed a decrease in affinity for proteases of genotypes 2 and 3 (K(i), 80 to 90 nM) compared to genotype 1 enzymes (K(i), 1.5 nM). BILN 2061 may be an antiviral agent for individuals infected with non-genotype-1 HCV.

Synthesis and SAR of acyclic HCV NS3 protease inhibitors with novel P4-benzoxaborole moieties.. . 11 Due to concern over cardiac issues in animals treated with macrocyclic BILN-2061, 12 newer acyclic inhibitors have recently been developed exemplified by BI-201335 13 and BMS-650032. 14 However.

BILN 2061 remains a potent inhibitor of these non-genotype-1 NS3-NS4A proteins, with K i values below 100 nM. This in vitro potency, in conjunction with the good pharmacokinetic data reported for humans, suggests that there is potential for BILN 2061 as an antiviral agent for individuals infected with non-genotype-1 HCV.

BILN 2061 in which the quinoline and thiazole nitrogens were 15 N-labeled was prepared, so that any interactions of these centers with alkaline earths could be probed. The known synthesis of BILN 2061 was followed, using 15 N-thiourea, 15 NH 4 OH, and 15 N- m -anisidine.

Additionally, the process chemistry team envisioned a S N Ar strategy to install the quinoline heterocycle, instead of the S N 2 strategy that they had employed for the synthesis of BILN 2061. This modification prevented the need for inefficient double inversion by proceeding through retention of stereochemistry at the C-4 position of the hydroxyproline moiety.

A multistep scalable synthesis of the clin. important hepatitis C virus (HCV) protease inhibitor BILN 2061 (1) is described. The synthesis is highly convergent and consists of two amide bond formations, one etherification, and one ring-closing metathesis (RCM) step, using readily available building blocks 2-5.

The first synthesis of stavudine was reported in 1966 as part of an investigation into the biosynthesis of 2'-deoxyribonucleotides, 65 and its activity against HIV was described 21 years later. 66,67 The metabolism of stavudine differs from zidovudine in that. which differs in its in vitro resistance profile from BILN 2061, is VX-950 (45) 78.

A new procedure for the practical synthesis of (S)-2-(cyclopentyloxycarbonyl)amino-8-nonenoic acid, a key building block for BILN 2061, an HCV NS3 protease inhibitor, has been developed. The key step features a kinetic resolution of racemic 2-acetylamino-8-nonenoic acid with acylase I.

Medical vegetation rich in vitamins and secondary metabolites have been source of inhibitors of the endogenous synthesis of cholesterol as BILN 2061 well as natural antioxidants (7 8 In Brazil the fruit ofCampomanesia adamantiumO.

BILN 2061 is a specific and potent peptidomimetic inhibitor of the HCV NS3 protease with IC50 of 3.0 nM. Buy HCV Protease inhibitor BILN 2061 (Ciluprevir, BILN 2061ZW) from AbMole BioScience.

Safety, Tolerance, and Pharmacokinetics of BILN 2061 ZW in Healthy Male Subjects, Combined With Preliminary Evaluation of Food Effect. The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government.

Compounds A-782759 (an N -1-aza-4-hydroxyquinolone benzothiadiazine) and BILN-2061 are specific anti-hepatitis C virus (HCV) agents that inhibit the RNA-dependent RNA polymerase and the NS3 serine protease, respectively. Both compounds display potent activity against HCV replicons in tissue culture.