Ravidasvir [Methyl
N-[(1S)-1-({(2S)-2-[5-(6-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]- 3-
methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}naphthalen-2-yl) -1H-
benzimidazol- 2-yl]pyrrolidin-1-yl}carbonyl)-2-methylpropyl]carbamate] is
an Nonstructural protein 5A (NS5A) inhibitor.
Ravidasvir: 2D and 3D Structure |
It is an antiviral agent that is
being developed as a potential treatment for hepatitis C virus infection. Ravidasvir has 50% inhibitory
concentrations (EC50 's)
values of 0.02-1.3 nM in replicon assays for HCV genotypes 1-7 (gt1-gt7).
Ravidasvir was developed
by Presidio Pharmaceuticals Inc, later Ascletis licensed it.
Ravidasvir is in Phase II clinical trials proving interferon
(IFN)-free regimen to treat chronic hepatitis C (CHC). Ascletis is now the
first Chinese company to file clinical trial applications in China for an
IFN-free regimen.
IUPAC Name: Methyl
N-[(1S)-1-({(2S)-2-[5-(6-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}naphthalen-2-yl)
-1H- benzimidazol- 2-yl]pyrrolidin-1-yl}carbonyl)-2-methylpropyl]carbamate
Common Name: PPI-668;
BI 238630; ASC16
Originator: Presidio
Pharmaceuticals Inc/Ascletis
One striking thing about this name, Ravidasvir (Ravidas+vir):
Ravidas was a North Indian Guru
mystic of the bhakti movement He was active in the 15th century CE. He is often
given the honorific title of Bhagat or Sant. He was a socio-religious reformer,
a thinker, a theosophist, a humanist, a poet, a traveller, a pacifist and a
spiritual figure.
Hepatitis C virus infection is a
major health problem worldwide and no vaccine has yet been developed against
this virus. The standard therapy of pegylated-interferon and ribavirin induces
serious side effects and provides viral eradication in less than 50% of
patients. Combination therapy of HCV including ribavirin and interferon are
currently is the approved therapy for HCV. Unfortunately, such combination
therapy also produces side effects and is often poorly tolerated, resulting in
major clinical challenges in a significant proportion of patients. The
combination of direct acting agents can also result in drug-drug interactions.
To date, no HCV therapy has been approved which is interferon free. There is
therefore a need for new combination therapies which have reduced side effects,
and interferon free, have a reduced emergence of resistance, reduced treatment
periods and/or and enhanced cure rates.
Nonstructural protein 5A (NS5A) is
a zinc-binding and proline-rich hydrophilic phosphoprotein that plays a key
role in Hepatitis C virus RNA replication.
A number of direct-acting
antiviral agents (DAAs) are under development for the treatment of chronic HCV
infection. These agents block viral production by directly inhibiting one of
several steps of the HCV lifecycle. several viral proteins involved in the HCV
lifecycle, such as the non-structural (NS)3/4A serine protease, the NS5B
RNA-dependent RNA polymerase (RdRp), and the NS5A protein, have been targeted
for drug development. Two NS3/4A protease inhibitors already approved for
clinical use, numerous other protease inhibitors are being developed as well as
inhibitors of viral replication, including nucleoside/nucleotide analogue
inhibitors of HCV RdRp, non-nucleoside inhibitors of RdRp, cyclophilin
inhibitors, and NS5A inhibitors.
Inhibition of NS5A at picomolar
concentrations has been associated with significant reductions in HCV RNA
levels in cell culture-based models, which makes these agents among the most
potent antiviral molecules yet developed.
Activity:
1H NMR (Estimated) for Ravidasvir |
Activity:
This NS5A inhibitor has been
shown to possess high efficacy against HCV genotype 1, with up to 3.7 log10 mean
HCV RNA reductions, in a Phase Ib clinical trial. Activity was demonstrated
against variants harbouring the L31M substitution. In an added genotype-2/3
cohort, the first 2 patients achieved mean 3.0 log10 RNA level
reductions [1].
Results from the Phase IIa study
involving a combination therapy with Faldaprevir and Deleobuvir plus Ravidasvir
came with positive news where the said combination cured 92 percent of those
with genotype 1a of hepatitis C virus (HCV) when given with ribavirin.
The results presented at the 49th annual meeting of the European
Association for the Study of the Liver (EASL) in London [2, 3].
The 36 study participants were
randomly dived into three even cohorts of 12 each: The first received 600 mg of
Deleobuvir twice a day as well as once-daily doses of Faldaprevir (120 mg),
Ravidasvir and Ribavirin. The second group received the same regimen except the
Faldaprevir dose was 400 mg. The third group took the regimen with the higher
dose of Faldaprevir, but without Ribavirin. All participants were treated for
12 weeks with follow up for next 24 weeks.
References:
1. Lalezari, J. P.; et. al. PPI-668, a potent new pan-genotypic HCV NS5A inhibitor: phase 1 efficacy and safety. Hepatology 2012, 56, 1065A-1066A.
2. ClinicalTrials.gov A Study of the Efficacy and Safety of PPI-668 (NS5A Inhibitor) Plus Sofosbuvir, With or Without Ribavirin, in Patients With Chronic Hepatitis C Genotype-4. NCT02371408 (retrieved on 24-03-2015)
3. ClinicalTrials.gov Study of PPI-668, BI 207127 and Faldaprevir, With and Without Ribavirin, in the Treatment of Chronic Hepatitis C. NCT01859962 (retrieved on 15-09-2015)
4. Lalezari, J.; et. al. High rate of sustained virologic response in patients with hcv genotype-1a infection: a phase 2 trial of faldaprevir, deleobuvir and ppi-668, with and without ribavirin. EASL-The International Liver Congress 2014 - 49th Annual Meeting of the European Association for the Study of the Liver London, United Kingdom April 9-13 (article here)
1. Lalezari, J. P.; et. al. PPI-668, a potent new pan-genotypic HCV NS5A inhibitor: phase 1 efficacy and safety. Hepatology 2012, 56, 1065A-1066A.
2. ClinicalTrials.gov A Study of the Efficacy and Safety of PPI-668 (NS5A Inhibitor) Plus Sofosbuvir, With or Without Ribavirin, in Patients With Chronic Hepatitis C Genotype-4. NCT02371408 (retrieved on 24-03-2015)
3. ClinicalTrials.gov Study of PPI-668, BI 207127 and Faldaprevir, With and Without Ribavirin, in the Treatment of Chronic Hepatitis C. NCT01859962 (retrieved on 15-09-2015)
4. Lalezari, J.; et. al. High rate of sustained virologic response in patients with hcv genotype-1a infection: a phase 2 trial of faldaprevir, deleobuvir and ppi-668, with and without ribavirin. EASL-The International Liver Congress 2014 - 49th Annual Meeting of the European Association for the Study of the Liver London, United Kingdom April 9-13 (article here)