Simeprevir

Description

In September 2013, simeprevir (also known as TMC435) was approved in Japan (trade name Sovriad?) for the treatment of genotype 1 hepatitis C virus (HCV) infection in combination with pegylated interferon and ribavirin (PR). Simeprevir was approved for the same indication in November 2013 in the United States (trade name Olysio?) and Canada (trade name Galexos?). Simeprevir is the third HCV PI to receive approval and was discovered from an effort to optimize a novel series of cyclopentane-core macrocyclic HCV PIs. Unlike the earlier PIs, simeprevir does not rely on formation of a covalent intermediate to inhibit the enzyme, but instead gains binding affinity through a large P2 quinoline substituent that occupies an extended S2 subsite of HCV protease by induced fit. This pocket is not occupied by inhibitors such as telaprevir and boceprevir. Other key features of simeprevir are truncation of the P3 capping group (the N-methyl amide), use of an acylsulfonamide as an acid isostere, and incorporation of an isopropylthiazole group to give improved permeability. Simeprevir is a potent NS3/4A PI (Ki=0.36 nM), with antiviral activity in the HCV replicon assay (genotype 1b EC₅₀=7.8 nM; genotype 1a EC₅₀=28.4 nM). It is 25-fold less potent against HCV genotype 2, >1000 less potent for HCV genotype 3, but has 3-fold better potency for HCV genotype 4.

Originator

Tibotec and Medivir (Ireland and Sweden)

Uses

Simeprevir-d3 is labelled Simeprevir (S466500) which is a hepatitis C virus (NS3/4A) protease inhibitor. Simeprevir (S466500) is used for the cure and treatment of hepatitis C.

Definition

ChEBI: Simeprevir is an azamacrocycle and a lactam.

brand name

Sovriad

Clinical Use

HCV NS3/4A serine protease inhibitor:
Treatment of hepatitis C in combination with other treatment

Synthesis

Commercial 2-methyl-3-methoxybenzoic acid (153) was treated with diphenylphosphorylazide (DPPA) and triethylamine to affect a Curtius rearrangement and the resulting isocyanate was trapped with t-butanol to produce the Boc-protected aniline 154 in quantitative yield. Upon removal of the Boc protecting group with TFA, the resulting aniline was reacted with boron trichloride followed by the addition of acetonitrile and aluminum trichloride to affect Friedel¨CCrafts acylation to give aminoacetophenone 155 in 40% yield. Acylation of the amino group with 4-isopropylthiazole- 2-carbonyl chloride (156) gave ketoamide 157 in 90% yield, which was treated with potassium tert-butoxide in t-butanol at 100 ?? to furnish quinolinol 158 in 88% yield.
Use of a ring closing metathesis approach, enabling the synthesis of the macrocyclic portion of the drug and ultimately simeprevir, is described. Hydrogenation of commercial trans-cyclopentanone-3,4-dicarboxylic acid (159) over Raney Ni in the presence of triethylamine followed by cyclization to the lactone using 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and N-methylmorpholine (NMM), and subsequent cinchonidine salt formation gave lactone acid 160 in 26% yield over the 3 steps in 97% ee. Next, amide coupling with N-methylhexenylamine using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), Fischer esterification, and subsequent introduction of the quinolinol fragment 158 under Mitsunobu conditions using triphenylphosphine (PPh3) and diisopropyl azodicarboxylate (DIAD) provided methyl ester 161 in 65% overall yield for the three steps. Saponification of the ester with lithium hydroxide followed by EEDQ-promoted coupling to (1R,2S)-1-amino-2-vinyl-cyclopropane ethyl ester (162) and Boc protection of the resulting amide gave the RCM substrate, diene 163 in 95% yield for the two steps. Macrocyclization of 163 using the second generation M2 catalyst under dilute concentration in refluxing toluene followed by acidic removal of the amide protecting group gave cycloalkene ester 164 in high yield. Saponification of the ester, activation of the resulting acid with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), and coupling with cyclopropylsulfonamide led to simeprevir (XXI) in high overall yield.

Drug interactions

Potentially hazardous interactions with other drugs
Anti-arrhythmics: possible increased risk of bradycardia with amiodarone.
Antibacterials: concentration possibly increased by clarithromycin - avoid; concentration of both drugs increased with erythromycin - avoid; concentration reduced by rifampicin and possibly rifabutin - avoid.
Antidepressants: concentration possibly reduced by St John’s wort - avoid.
Antiepileptics: concentration possibly reduced by carbamazepine, fosphenytoin, oxcarbazepine, phenobarbital, phenytoin and primidone - avoid.
Antifungals: concentration possibly increased by fluconazole, itraconazole, ketoconazole, posaconazole and voriconazole - avoid.
Antivirals: concentration of both drugs increased with darunavir - avoid; concentration reduced by efavirenz; avoid with etravirine; concentration possibly reduced by nevirapine - avoid; concentration increased by ritonavir - avoid.
Ciclosporin: avoid concomitant use, increased simeprevir concentration.
Cobicistat: concentration possibly increased by cobicistat - avoid.

Metabolism

Hepatically metabolised. In vitro experiments with human liver microsomes indicated that simeprevir primarily undergoes oxidative metabolism by the hepatic CYP3A4 system.
Elimination of simeprevir occurs via biliary excretion. Following a single oral administration of 200 mg [14C]-simeprevir to healthy subjects, on average 91% of the total radioactivity was recovered in faeces. Unchanged simeprevir in faeces accounted for on average 31% of the administered dose. Renal clearance plays an insignificant role in its elimination.