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Research Article | DOI: https://doi.org/10.31579/2690-1919/043
Head R&D-QC/QA, IPL Research Centre, India.
*Corresponding Author: Krishnasarma Pathy, Head R&D-QC/QA, IPL Research Centre, India
Citation: Krishnasarma Pathy (2020) Can Body Height Be Used to Predict Knee Implant Sizes? J Clinical Research and Reports, 3(4); DOI:10.31579/2690-1919/043
Copyright: © 2020 Krishnasarma Pathy. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received: 12 February 2020 | Accepted: 06 March 2020 | Published: 11 March 2020
Keywords: hepatitis C NS3 protease, quinoline P2 substituent ; pyrazinone macrocyclic inhibitors; ptotease inhibitors
Chronic hepatitis C virus (HCV) is considered as a major cause of liver diseases. The standard treatment of HCV infection is a combination of direct-acting antiviral agents (DAAs). Relapse is defined where HCV RNA remained undetectable at the end of therapy but rebounded to pre-treatment levels once DAA therapy was discontinued. This study was performed summarizes our current understanding of HCV treatment, particularly with those of NS3 inhibitors and patent status and approvals of Simeprevir
Simeprevir (formerly TMC435) is a second-generation HCV NS3/4A serine protease inhibitor marketed under the trade names Olysio, Galexos (in Canada) and Sovriad (in Japan). Hepatitis C virus (HCV) is the major etiological agent of 90% of all cases of non-A, non- 13 hepatitis. The incidence of HCV infection is becoming an increasingly severe public health concern with 2-15% individuals infected worldwide. While primary infection with HCV is often asymptomatic, most HCV infections progress to a chronic state that can persist for decades. Of those with chronic HCV1 infections, it is believed that about 20- 50% will eventually develop chronic liver disease (e.g. cirrhosis) and 20-30% of these cases will lead to liver failure or liver cancer. As the current HCV-infected population ages, the morbidity and mortality11 associated with HCV are expected to triple. The use of protease inhibitors, particularly those selectively targeting HCV serine protease, has great potential to be useful in treating HCV infections in patients by inhibiting HCV replication.
CHARACTERIZATION OF RESISTANCE ASSOCIATED VARIANTS SELECTED IN GT1, GT2 AND GT3 REPLICONS BY THE HCV NS3/4A PROTEASE INHIBITOR
In the mid-1970s, it was noticed that supply of blood was contaminated with an unidentified agent causing post transfusion non-A, non-B hepatitis. This unknown infectious agent struck intravenous drug2 users and blood transfusion recipients. The offender agent identified in 1989 was hepatitis C virus (HCV) and the first sequences of HCV were reported HCV is one of the leading agents that cause liver failure, and hepatocellular carcinoma and is the most relevant reason for liver transplantation. HCV infects about 3% of the world population; 130–200 million people are estimated to be chronically infected globally. Alarming news is that 350,000 people worldwide die from HCV-related disease every year. For more than 20 years, HCV has been taking the attention of the health professionals, and now, well recognized that HCV is actually a major global health problem. Recently, health professionals determined the worldwide prevalence of HCV 3in comparison with HIV13. The global prevalence of HCV estimates is 400,000 chronically infected subjects in Australia and Oceania, 14 million in the United States of America, 16 million in the Middle East, 17.5 million in Europe, 28 million in Africa, and 83 million in Asia. Therefore, novel and effective inventions with fewer adverse effects are required for the prevention and control of HCV. The main goal of this review article is to be updated with the current treatments of HCV, putting an emphasis4 on the HCV NS3 protease and NS3 helicase inhibitors.
Simeprevir was approved in 2013 for use in the United States, Japan and Canada as a combination treatment for chronic genotype 1 HCV2 infection. The Committee for Medicinal Products for Human Use of the European Medicines Agency has authorized use of simeprevir in the European Union in a combination treatment for chronic HCV.
On November 5, 2014, the U.S. FDA approved the use of simeprevir in combination with sofosbuvir4 as an all-oral, interferon- and ribavirin-free treatment option for patients with genotype 61 chronic hepatitis 2C. The recommended treatment duration of simeprevir with sofosbuvir5 is 12 weeks for patients without cirrhosis or 24 weeks for patients with cirrhosis..
Simeprevir reaches high sustained virologic 10response when given in combination with pegylated interferon and ribavirin in patients with HCV genotype6 1 infection. Simeprevir is considered a “second-generation compound” as it is a peptidomimetic compound, a small protein-like chain designed 15to mimic a peptide. It was developed by Medivir and Johnson & Johnson's pharmaceutical division, Janssen Pharmaceuticals Inc. (hereby referred to as the ‘Sponsor’).
Patent application WO2007014926A1 relates to the base compound of simeprevir. The application claims a general structural formula of macrocyclic compounds14 which act as inhibitors of HCV infections. The application also claims a process for preparation of simeprevir and its method of use. It includes a 21pharmaceutical combination of simeprevir with ribavirin. This patent, if granted, serves as a blocking patent preventing any other competitor from making the product. The claims are very broad, covering a Markush structure of antiviral agents along with its process of preparation and method of use.
There are three patents granted in the United States: US8148399B2, US8153800B2 and US8349869B2. US8148399B2 relates to the base compound of simeprevir. US8153800B2 is a divisional of US8148399B2 and relates to the macrocyclic compounds as well as processes for preparing these compounds and compositions. US8349869B2 is a divisional of US8148399B2 and relates to a macrocyclic compound, it’s N-oxide, pharmaceutically acceptable salt or stereoisomer. It claims a combination of the compound with interferon-α, pegylated interferon-α, and/or ribavirin.
Patent application WO2010072742A1 is a process patent. The application covers a process for the preparation of antiviral agents as well as intermediates for the preparation of bicyclic lactone amides, which are then converted into the desired products used for treating HCV infections, particularly simeprevir. The process claims are moderately narrow, claiming the process and various intermediates for preparation of antiviral compounds.
Patent application WO2011113859A1 covers a process for the preparation of intermediates useful in the preparation of macrocyclic compounds which are used for treating HCV infections, preferably simeprevir. The application also claims various intermediate compounds.
The patent application WO2008092955A1 covers processes for preparing and further processing quinoline compounds to obtain the desired product, preferably simeprevir.
Patent application WO2013041655A1 is a process patent, covering processes for the preparation of salts of intermediate compounds used in the synthesis of simeprevir16. The claimed process is a multi-step synthesis involving a number of reactants.
Patent application WO2013061285A1 is a process patent, claiming an improved process for the preparation of intermediate compounds used in the synthesis16 of HCV inhibitor compounds, particularly simeprevir. The process is claimed to be a straightforward, quick and economic procedure to formulate intermediates for the production of simeprevir. The application also claims various new intermediate compounds.
This patent is listed in the US Orange Book with patent numbers US7671032. Patent application WO2005073195A2 is a product patent, claiming simeprevir derivatives, their salts and prodrugs along with the compositions comprising them, as well as the use of the derivatives for the treatment or prevention of flavivirus infections including HCV infection. These compounds are stated to be useful as NS3 serine protease inhibitors. The application discloses a Markush structure of the general formula along with various substituents.
Patent application WO2008092954A2 is a formulation patent, originally filed by Tibotec Pharmaceuticals, now part of Janssen Pharmaceuticals. The application claims a crystalline form of a substituted macrocyclic compound, preferably simeprevir, for use in HCV treatment. The application also claims a combination of the compound with a pharmaceutically acceptable excipient. The patent is not relevant to the current version of simeprevir sold by the Sponsor since the European Medicines Evaluation Report states that the crystalline form of the drug is poorly soluble. Therefore, an amorphous form of simeprevir was developed. Patent application WO2010031829A1 is a formulation patent, claiming a combination of two compounds, simeprevir and a nucleoside, as well as a combination of these compounds with ribavirin or pegylated interferon. The combination is claimed to produce a synergetic effect to treat HCV infections. Patent application WO2010097229A2 is a product patent, claiming a sodium salt of simeprevir in solid amorphous form, useful for the treatment of HCV infections. Patent application WO2011128378A1 is a formulation patent, claiming a combination of a macrocyclic HCV protease inhibitor, a macrocyclic18 non-nucleoside HCV polymerase inhibitor, and a nucleoside HCV polymerase inhibitor. It is preferably a combination of TMC-647055 and simeprevir. The claims are limited to a combination of specific compounds. TMC647055 is a potent non-nucleoside inhibitor of the HCV NS5B polymerase currently developed by Janssen.
Patent application WO2014033668A2 claims a combination compound comprised of simeprevir, ritonavir and TMC-647055 for treating HCV infection. As per the WIPO ISR, the application is novel and not obvious in comparison to the closest prior art retrieved during the search.
This patent collection comprises 12 different patents (patent families). The majority of these patent applications are still pending in the respective national and regional patent offices
HCV NS3 protease inhibitor simeprevir
During the development of the now approved HCV NS3 protease inhibitor simeprevir, which contains a quinoline P2 substituent other P2heterocycles 17were also evaluated (e.g. pyrimidines5 , . The etherlinkage found in simeprevir, which connects the P2 core and the P2 heterocyclic
A urea moiety in the C3 position improved both stability and inhibitory potency compared with the carbamate analog. Inhibitors containing P4P5-ureas were prepared and evaluated and indicated allowance for substituents in this area. Relocation of the P2 group to the R6 position was well accepted and resulted in achiral inhibitors with improved inhibitory potencies for elongated R6 moieties. Moreover, the R6 substituents influenced the PK, with favorable properties for a pyridyl moiety.
The resistance profile for this class of inhibitors showed retained inhibitory potencies against known drug-resistant variants of the virus, i.e. R155K, A156T and D168V. Initial evaluation against genotype 3a displayed promising inhibitory potencies for a set of inhibitors with Ki values 0.6-3.4 µM. • Based on evaluation of several P1P1’ building blocks, preliminary results suggested that the acyl sulfonamide did not improve the inhibitory potency. The P1’ aryl did not appear to have any specific interactions with the S1’ pocket, as supported by comparable inhibitory potencies for truncated derivatives. It was found that the P1 aryl in combination with the P3 pyrazinone and a C3 urea were important for sub-micro molar Ki values, suggesting that this could be the new lead structure.
An efficient Pd-catalyzed C-N urea arylation to the C3 position of the pyrazinone was developed and successively applied to inhibitors with elongated P4P5 urea substituents. In line with our interest in identifying carboxylic acid bioisosteres, a novel Pd-catalyzed carbonylation protocol for sulfinamides yielding acyl sulfinamides was developed Paper was based on two drug discovery projects within the HCV area, both aiming to inhibit the drug target, NS3 protease. The criteria differed with respect to the various stages of discovery they represented. In the P2 quinazoline macrocyclic18 series, the lead structure was optimized for improved PK properties along with sub-nano molar Ki and Nano molar EC50 values. The pyrazinone series, on the other hand, represents an early stage of drug discovery aiming for new lead compounds, which could be further optimized into coming generation of HCV NS3 protease inhibitors. The main findings are summarized below
Crystal structure of HCV NS3/NS4A protease in complex with TMC-435 (PDB ID: 3KEE) [19]. Binding subsites of S1’
S4 in the active site are indicated on the surface representation and labelled in black. The bound inhibitor, TMC-435, is
shown as a ball-and-stick model and is colored by atom type. For clarity, hydrogen atoms are omitted.
The Functions of HCV NS3 Proteins
NS3 is a multifunctional protein with serine protease activity at the N-terminal and a nucleoside-triphosphatase- (NTPase-) dependent RNA helicase activity (NS3 NTPase/helicase) at the C-terminal (aa 181–631). Both enzyme activities have been well defined and high-resolution structures have been solved The C-terminus of NS3 encodes a DExH/D-box RNA helicase. NS3 helicase hydrolysed NTP as an energy source to unwind double-stranded RNA in a 3′ to 5′ direction during replication of 12viral genomic RNA Structural analysis of NS3 revealed the unidirectional translocation and proposed a new function of NS3 as translocase, considering feasible strategies for developing specific inhibitors to block the action of NS3 helicase. The activity of NS3 helicase can be regulated by interactions between the serine protease and helicase domains of NS3, indicating that these two enzyme activities may be somehow coordinated during replication. The function of the HCV helicase is unknown; it has been shown that without functional helicase domains, HCV cannot replicate in cells. It may be involved in the initiation of RNA synthesis on the HCV genome RNA, which contains stable 3′-terminal secondary structure in dissociation of nascent RNA strands from their template during RNA synthesis or in displacement of proteins or other trans-acting factors from the RNA genome. It has been now well recognized that both activities of NS3 protein are required for the replication of virus; they are considered as attractive target sites for the development of direct-acting antivirals (DAAs) therapies. NS5B is the viral11 RNA-dependent RNA polymerase, another promising anti-HCV target site. NS5A is a phosphoprotein specifically capable of interacting with the 3′-NTR of the HCV genome, other non-structural proteins, and numerous cellular proteins. NS5A also functions in virus assembly. NS4B is an integral membrane protein that is required for the assembly of the “membranous web,” the organelle used for RNA replication. NS4A is a cofactor for NS3 that directs the localization of NS3 and modulates its enzymatic activities
Pharmacokinetic Aspects in Drug Discovery
A revealing paper published in 1988 presented the reasons for the failure of drugs in development. Alarmingly, 39% of drugs failed due to poor PK properties and bioavailability. Years of invested money and time were lost, and the introduction of new drugs on the market was delayed. This ultimately affected the patients in need of new pharmaceuticals. Contemporary drug discovery and development has a different approach. At its best, a drug discovery program is a highly iterative process,17,19 where properties such as solubility, permeability and metabolic stability are evaluated in parallel with optimizations in terms of binding to the target. A less active compound could have advantageous PK properties which enable a better in vivo therapeutic response and, eventually, might offer more convenient dosage regimens for the patient. A successful research program needs to consider and attempt to anticipate how the various properties of a drug cooperate at its final destination inside the human body .Lipinski’s well known “rule-of-five” has, since it was presented in 1997,guided the choice of compounds that will proceed in the discovery process. While favourable PK properties and solubility can be predicted from the molecular qualities, the emerging area of demanding and novel targets as well as poor outcomes from big pharma have challenged researchers to think “outside the box”, and this can be rewarding. In the HCV research field, for example, the approved HCV NS3 protease anti-HCV drugs violate at least one of the rules, since they have a molecular weight of >700. One could consider the drug-like properties as guidelines but should also bear in mind that the success of a drug depends on how well various properties are balanced with each other. Moreover, oral drug space is likely to expand with improved formulation techniques.
Harmonizing Antiviral Potency with PK Properties in the Development of HCV NS3
ProteaseInhibitors :
During the development of the now approved HCV NS3 protease inhibitor simeprevir, which contains a quinoline P2 substituent other P2heterocycles17 were also evaluated (e.g. pyrimidines. The ether linkage found in simeprevir, which connects the P2 core and the P2 heterocyclic group, was replaced with a carbamate moiety (II, Figure 14) in another series.98 However, neither the pyrimidine- nor the carbamate-linked P2aromatic substituents yielded optimal properties for the inhibitors.29During these explorations, a novel P2 quinazoline substituent was identified (III, Figure 14); this was combined with a cyclopentane core (as in simeprevir) and a proline urea core in further optimizations. The quinazoline substituent was modified with the goal of balancing antiviral potency withthe PK properties.
Initial modifications on the quinazoline substituent. Ki (NS3fl1a): inhibition constant. EC50 (NS31b): cell-based activity. The cut-off values for stability in human liver microsomes (HLM), intrinsic clearance (μL/min/mg): Clint< 30>no risk; 30 < Clint>moderate risk; Clint > 92: high risk. The cut-off values for Caco-2 permeability (cm/s): Papp < 2>-6: low; 2×10-6 < Papp>-6: moderate; Papp > 20 × 10-6: high. Interestingly, the introduction of a thiazolyl substituent reduced the enzyme- and the cell-based activity drastically (4 and 5), in contrast to the outcomes found in the quinoline series, where such a moiety improved the potency.A likely reason for the lower potency is that repulsion between the hetero atoms in the thiazolyl moiety and the nitrogens in the quinazoline impeded the bioactive co-planar conformation of the thiazolyl substituent, leading to reduced interactions with the enzyme
A similar reason could possibly explain the drastic decrease in both enzyme and cell-based assays for compounds 6 and 7, i.e. that the non-aromatic rings did not adopt a bioactive conformation, leading to reduced potencies. The main improvements for the initial optimizations were the addition of a methoxy group in position 7 of the quinazoline, which improved the cell based potency (2), and the introduction of a fluoro moiety on the phenyl group, which increased the metabolic stability.
The direct-acting antiviral agents (DAAs), particularly NS3 protease inhibitors, telaprevir and boceprevir, which were approved in combination with current SOC (peg-IFN and ribavirin) for the treatment of HCV infection that significantly increased SVR, have opened a new window in HCV therapy. However, the side effects associated with this new therapy are a questionable maker. Anemia is the most frequent adverse effects with either telaprevir or boceprevir. They also exhibit strong inhibitory effect against an important drug metabolism enzyme, cytochrome P4503A4 (CYP3A4) resulting in the development of drug-drug interactions. In addition to drug resistance, the efficacies of these inhibitors differ significantly between HCV genotypes31. It is well known that IFN itself has significant side effects. Another important issue arises with their short half-life and frequent dosing. With the advent of different small classes of DAAs, the future aim is to introduce an IFN-free regimen, oral cocktails of DAAs. The proof-of-concept studies presented some promising data confirming that the achievements of SVR without introducing IFN may be feasible. Thus, the combination of host and viral targeted inhibitors could be an attractive strategy in maximizing antiviral efficacy.
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