Background &Aims: Novel, potent, and well-tolerated hepatitis C virus (HCV) drugs are needed. BILN 2061 is a potent and specific inhibitor of HCV serine pro tease in vitro. Preclinical toxicology data and studies ...Background &Aims: Novel, potent, and well-tolerated hepatitis C virus (HCV) drugs are needed. BILN 2061 is a potent and specific inhibitor of HCV serine pro tease in vitro. Preclinical toxicology data and studies in healthy volunteers supported the administration of BILN 2061 to patients with HCV infection. Methods: The antiviral efficacy, pharmacokinetics, and tolerability of 25, 200, and 500 mg BILN 2061 twice daily given as monotherapy for 2 days in 31 patients infected with chronic genotype 1 HCV infection and with minimal liver fibrosis (Ishak score of 0-2) were assessed in a placebo-controlled, doubleblind pilot study. In 2 subsequent placebo-controlled studies of similar design, 200 mg BILN 2061 twice daily was administered for 2 days to 10 patients with advanced liver fibrosis (Ishak score of 3 or 4) and to 10 patients with compensated cirrhosis (Ishak score of 5 or 6). Results: Viral RNA reductions of 2-3 log10 copies/mL were achi eved in most of the patients. There was a trend toward a higher number of patients receiving 500 mg BILN 2061 achieving a viral RNA reduction ≥3 log10 copies/mL as compared with patients receiving 25 mg BILN 2061. Advanced fibrosis or comp ensated cirrhosis did not affect the antiviral efficacy of BILN 2061. BILN 2061 was well tolerated in all studies. Conclusions: BILN 2061 is a well-tolerated a nd very active compound that reduced serum viral RNA concentrations after 2 days of treatment in patients infected with genotype 1 HCV independent of the degree of fibrosis. Nevertheless, further clinical trials are on hold pending resolution of animal toxicity is sues.展开更多
A concise synthesis of BILN 2061 was achieved through more efficient installation of P2 4-quinoline moiety via SN2 displacement of the β-OBs group located on the 4-hydroxyl proline intermediate, which was prepared fr...A concise synthesis of BILN 2061 was achieved through more efficient installation of P2 4-quinoline moiety via SN2 displacement of the β-OBs group located on the 4-hydroxyl proline intermediate, which was prepared from 4-α-hydroxyl proline analog via Mitsunobu reaction with inversion of stereochemistry. In addition, a short and practical synthesis for P3 unit is also described herein. Final assembly of four fragments for BILN 2061 was achieved with an overall yield of 58% in 4 steps from P1 to 15a. Furthermore several analogs of BILN 2061 （WX-I--WX-5） containing modifications on P3 unit were synthesized successfully using the same synthetic route as described for the parent inhibitor BILN 2061.展开更多
文摘Background &Aims: Novel, potent, and well-tolerated hepatitis C virus (HCV) drugs are needed. BILN 2061 is a potent and specific inhibitor of HCV serine pro tease in vitro. Preclinical toxicology data and studies in healthy volunteers supported the administration of BILN 2061 to patients with HCV infection. Methods: The antiviral efficacy, pharmacokinetics, and tolerability of 25, 200, and 500 mg BILN 2061 twice daily given as monotherapy for 2 days in 31 patients infected with chronic genotype 1 HCV infection and with minimal liver fibrosis (Ishak score of 0-2) were assessed in a placebo-controlled, doubleblind pilot study. In 2 subsequent placebo-controlled studies of similar design, 200 mg BILN 2061 twice daily was administered for 2 days to 10 patients with advanced liver fibrosis (Ishak score of 3 or 4) and to 10 patients with compensated cirrhosis (Ishak score of 5 or 6). Results: Viral RNA reductions of 2-3 log10 copies/mL were achi eved in most of the patients. There was a trend toward a higher number of patients receiving 500 mg BILN 2061 achieving a viral RNA reduction ≥3 log10 copies/mL as compared with patients receiving 25 mg BILN 2061. Advanced fibrosis or comp ensated cirrhosis did not affect the antiviral efficacy of BILN 2061. BILN 2061 was well tolerated in all studies. Conclusions: BILN 2061 is a well-tolerated a nd very active compound that reduced serum viral RNA concentrations after 2 days of treatment in patients infected with genotype 1 HCV independent of the degree of fibrosis. Nevertheless, further clinical trials are on hold pending resolution of animal toxicity is sues.
文摘A concise synthesis of BILN 2061 was achieved through more efficient installation of P2 4-quinoline moiety via SN2 displacement of the β-OBs group located on the 4-hydroxyl proline intermediate, which was prepared from 4-α-hydroxyl proline analog via Mitsunobu reaction with inversion of stereochemistry. In addition, a short and practical synthesis for P3 unit is also described herein. Final assembly of four fragments for BILN 2061 was achieved with an overall yield of 58% in 4 steps from P1 to 15a. Furthermore several analogs of BILN 2061 （WX-I--WX-5） containing modifications on P3 unit were synthesized successfully using the same synthetic route as described for the parent inhibitor BILN 2061.
