1256388-51-8 Usage
Description
Ledipasvir is a potent NS5A inhibitor that is approved for use in
combination with sofosbuvir, a nucleotide inhibitor of viral polymerase,
for the treatment of chronic hepatitis C virus genotype 1
infection. This combination was discovered and developed
at Gilead Sciences and is marketed as the fixed combination with
brand name of Harvoni.
Uses
Ledipasvir is most commonly used in combination with sofosbuvir for treatment in chronic hepatitis C genotype 1 patients. It inhibits an important viral phosphoprotein, NS5A, which is involved in viral replication, assembly, and secretion.
Definition
ChEBI: Ledipasvir is a benzimidazole derivative that is used in combination with sofosbuvir (under the trade name Harvoni) for the treatment of chronic hepatitis C genotype 1 infection. It has a role as an antiviral drug and a hepatitis C protease inhibitor. It is a carbamate ester, a L-valine derivative, a bridged compound, a carboxamide, a benzimidazole, a member of fluorenes, an organofluorine compound, a member of imidazoles, a N-acylpyrrolidine and an azaspiro compound.
Pharmacokinetics
Oral bioavailability of sofosbuvir is at least 80% based on urinary recovery. Ledipasvir also is well absorbed orally. Approximately 65% of sofosbuvir is bound to human plasma protein, and virtually all of ledipasvir is plasma protein bound.The sofosbuvir Tmax is 0.5 to 2 hours, with peak plasma concentration of the active metabolite occurring 2 to 4 hours after dosing. The Tmax for ledipasvir is 4 to 4.5 hours. The terminal halflife for sofosbuvir and its active metabolite are 0.4 and 27 hours, respectively, and the terminal half-life for ledipasvir is 47 hours. Sofosbuvir primarily is eliminated in the urine, whereas ledipasvir elimination occurs primarily through the biliary tract. Eighty percent of sofosbuvir is recovered in the urine, primarily as the active metabolite, and 86% of ledipasvir is recovered in the feces.
Synthesis
The synthesis of
the spirocyclopropane proline intermediate 136 is described in
Scheme above. Bis-iodination of cyclopropane-1,1-diyldimethanol
(131) in the presence of triphenylphosphine gave diiodide 132 in
70% yield. N-Boc-glycine ethyl ester (133) was then treated with
sodium hydride followed by diiodide 132 to give the protected proline
analog 134 in 61% yield. Saponification of the ester followed by
a classical resolution with (1S,2R)-amino-indanol gave enantomerically
pure salt 135. Liberation of the free acid with 1 M HCl followed
by treatment with potassium tert-butoxide provided
enantiopure potassium salt 136 in high yield.
Iodination of 2-bromofluorene
(137) produced aryl iodide 138 in 95% yield, which was
then treated with lithium hexamethyldisilazide and N-fluorobenzenesulfonimide
(NFSI) to give the difluoro intermediate 139 in
82% yield. Formation of the Grignard reagent of 139 through reaction
with isopropylmagnesium chloride followed by condensation
with Weinreb amide 140 gave chloroketone 141 in 71% yield. The
potassium salt of the cyclopropyl proline intermediate 136 was coupled with 141 to give keto ester
142 in high yield. Heating 142 with ammonium acetate resulted
in formation of the imidazole ring in intermediate 143 in 77%
yield.
Commercially available (1R,3S,4S)-N-Boc-2-azabicyclo
[2.2.1]heptane-3-carboxylic acid (144) was coupled to 4-bromo-
1,2-benzenediamine (145) using EDC/HOBt to give a mixture of
amides 146a/146b in 72% yield. Heating mixture 146a/146b with
acetic acid affected cyclization to benzimidazole 147 in 94% yield.
Palladium mediated coupling of bromide 147 to bis(pinacolato)diboron
gave intermediate 148 which was then coupled in the same
reaction vessel to bromide 143. This was
followed by formation of the oxalate salt to give the protected central
core of ledipasvir (149) in good overall yield. Removal of the
amine protecting groups gave diamine 150 which was coupled to
two equivalents of Moc-valine (151) via EDC/HOBt to give ledipasvir
XVII in 73% yield.
Clinical claims and research
Ledipasvir is an HCV NS5A inhibitor, while sofosbuvir inhibits HCV NS5B polymerase. These two agents are combined in a fixed-dose combination tablet marked under the trade name Harvoni? for the treatment of patients with chronic HCV. A phase I study in healthy subjects demonstrated that a moderate-fat (600 kcal, 25–30% fat) or high-fat, high-calorie (1000 kcal, 50% fat) meal did not significantly alter the Cmax, AUC0-∞, or tmax of ledipasvir–sofosbuvir. A post hoc analysis of the phase III clinical trial data was performed to evaluate the effect of food on the pharmacokinetics and clinical outcomes of ledipasvir–sofosbuvir and revealed no significant effects.Ledipasvir demonstrates pH-dependent solubility in vitro and therefore was evaluated in two phase I studies examining the effects of coadministration with a histamine H2-receptor antagonist (famotidine 40 mg) and a proton-pump inhibitor (omeprazole 20 mg). Administration of a single dose of the combination product ledipasvir–sofosbuvir with famotidine or omeprazole and food did not significantly alter the AUC or Cmax of either agent. Ledipasvir–sofosbuvir may be administered without regard to meals or timing of acid-reducing agents.
Mode of action
Ledipasvir is a potent inhibitor of HCV nonstructural protein 5A (NS5A), a viral phosphoprotein that plays an important but poorly understood role in viral replication, assembly, and secretion. ;Ledipasvir is approved for the treatment of genotype 1 HCV. Its safety and efficacy have not been fully established for genotypes 2 through 6. NS5A amino acid substitutions Y93H (in genotypes 1a and 1b) and Q30E (in genotype 1a) significantly reduce susceptibility to ledipasvir in cell culture and in clinical studies. Other amino acid substitutions observed in virologic treatment failures are K24R, M28T/V, Q30H/K/L (genotype 1a), and L31V/M/I (genotype 1b). Viruses with these resistance-associated mutations remained susceptible to sofosbuvir.
references
[1] hernandez d et al. , natural prevalence of ns5a polymorphisms in subjects infected with hepatitis c virus genotype 3 and their effects on the antiviral activity of ns5a inhibitors. j clin virol. 2013, 57(1): 13-8.[2] gao m et al. , chemical genetics strategy identi?es an hcv ns5a inhibitor with a potent clinical effect. nature. 2010, 465: 96-100.[3] lawitz e j et al. , a phase 1, randomized, placebo-controlled, 3-day, dose-ranging study of gs-5885, an ns5a inhibitor, in patients with genotype 1 hepatitis c. j hepatol. 2012, 57(1): 24-31.
Check Digit Verification of cas no
The CAS Registry Mumber 1256388-51-8 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 1,2,5,6,3,8 and 8 respectively; the second part has 2 digits, 5 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 1256388-51:
(9*1)+(8*2)+(7*5)+(6*6)+(5*3)+(4*8)+(3*8)+(2*5)+(1*1)=178
178 % 10 = 8
So 1256388-51-8 is a valid CAS Registry Number.
1256388-51-8Relevant articles and documents
Ledipasvir preparation method
-
, (2018/05/16)
The invention discloses a Ledipasvir preparation method. The Ledipasvir preparation method includes steps: (1) Ledipasvir intermediate product 1-LD-B preparation; (2) Ledipasvir intermediate product 2-LD-E preparation; (3) Ledipasvir intermediate product 3-LD-F preparation; (4) Ledipasvir intermediate product 4-LD-J preparation; (5) Ledipasvir intermediate product 5-LD-L preparation; (6) Ledipasvir-LD-Q preparation. The Ledipasvir preparation method has advantages of technical maturity and stability, product quality stability, safety and reliability in production process and suitableness for industrial production.
PROCESS FOR PREPARATION OF LEDIPASVIR
-
, (2017/09/15)
The present invention relates to a process for the preparation of ledipasvir a compound of formula I, which is useful as an antiviral agent. The present invention also provides ledipasvir phosphate.
Preparation method of ledipasvir and intermediate for preparing ledipasvir
-
, (2017/07/26)
The invention provides a preparation method of a ledipasvir key intermediate. The preparation method comprises the following steps: taking a compound with the structure shown as the formula I and 2-bromo-7-chloro-9-fluorene are used as starting materials and preparing a compound with the structure shown as the formula II and 2-bromo-7-chloro-9,9-difluoro-9H-fluorene respectively; carrying out a carbon-hydrogen activation coupling reaction, a Suzuki coupling reaction and a deprotection reaction to obtain the key intermediate for synthesizing ledipasvir, namely, a compound with the structure shown as the formula VIII; carrying out a condensation reaction on the key intermediate and Moc-L-valine, so as to obtain the ledipasvir. The preparation method of the ledipasvir key intermediate, provided by the invention, is simple and has a few of steps; the key compound, namely the 2-bromo-7-chloro-9,9-difluoro-9H-fluorene (formula IV), can be prepared into the key intermediate VIII for synthesizing ledipasvir through a three-step reaction; the utilization rate of a fluorine compound is improved and the preparation cost is reduced.
