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Anti-Infective Agents
Published in Radhwan Nidal Al-Zidan, Drugs in Pregnancy, 2020
Risk Summary: The reproduction studies in animals have shown no evidence of fetal harm or impaired fertility. The pregnancy experience in humans is adequate to exhibit that the embryo-fetal risk is nonexistent or very low. However, Telaprevir is contraindicated during pregnancy if taken in combination with Ribavirin and peginterferon alfa.
Hydrolytic Enzymes for the Synthesis of Pharmaceuticals
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Sergio González-Granda, Vicente Gotor-Fernández
Telaprevir is a serine protease inhibitor approved for the treatment of hepatitis C patients. The desymmetrisation of a meso-diol precursor using vinyl acetate as both acyl donor and solvent, and the has been efficiently catalysed by Amano PS lipase supported on Celite (Scheme 9.36), obtaining the (1S,2R)-monoacetate in 97% yield and 97% ee after 17 h at 0°C (Moni et al., 2015). In a complementary approach, its enantiomer (1R,2S)-monoacetate was obtained by chemical acetylation of the diol and subsequent desymmetrisation using the same enzyme in hydrolytic conditions, leading to the hydroxy acetate in 78% yield and 95% ee after 21 h at 20°C. Desymmetrisation of meso-compounds by independent acetylation or hydrolysis using Amano PS towards the formation of Telaprevir.
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Published in Caroline Ashley, Aileen Dunleavy, John Cunningham, The Renal Drug Handbook, 2018
Caroline Ashley, Aileen Dunleavy, John Cunningham
The pharmacokinetics of telaprevir were assessed after administration of a single dose of 750 mg to HCV-negative subjects with severe renal impairment (CRCL<30 mL/min). The mean telaprevir Cmax and AUC were 10% and 21% greater, respectively, compared to healthy subjects.
Multicomponent reactions (MCR) in medicinal chemistry: a patent review (2010-2020)
Published in Expert Opinion on Therapeutic Patents, 2021
Hafiza Amna Younus, Mariya Al-Rashida, Abdul Hameed, Maliha Uroos, Uzma Salar, Sobia Rana, Khalid Mohammed Khan
MCRs have rendered shorter, convergent, and cheaper synthesis of lead compounds in medicinal chemistry. An excellent representative is the recently approved HCV protease inhibitor Incivek® (Telaprevir). Industrial production of this complex compound was relying on a lengthy, highly linear multistep sequential strategy following standard peptide chemistry exceeding 20 synthetic steps. Orru et al. [46,47] reported that they successfully reduced the lengthy steps and complexity of the synthesis of Incivek (Telaprevir) by almost half. It was done by using biotransformation and two multicomponent reactions as the key steps (Scheme 3). Riva et al. came up with another MCR approach toward Incivek with an enantioselective enzymatic desymmetrization approach [48]. Convergent synthesis of the schistosomiasis drug Biltricide® (Praziquantel) using key Ugi and Pictet-Spengler reactions (Scheme 4) is another example of MCRs advances in medicinal chemistry [49].
Natural products for the management of the hepatitis C virus: a biochemical review
Published in Archives of Physiology and Biochemistry, 2020
Walid Hamdy El-Tantawy, Abeer Temraz
Swietenia macrophylla, belongs the Meliaceae family, used as a folk medicine in Malaysia. Treatment of subgenomic replicon harboring cells with 3-hydroxy caruilignan C (3-HCL-C) isolated from S. macrophylla stems caused a reduction of protein and RNA levels and 3-HCL-C exhibited high anti-HCV activity at nontoxic concentrations, with an EC50 value of 10.5 ± 1.2 μM. Moreover, combinations of 3-HCL-C and interferon-α (IFN-α), HCV NS5B polymerase inhibitor (2′-C-methylcytidine; NM-107) or an HCV NS3/4A protease inhibitor (Telaprevir; VX-950) increased the suppression of HCV RNA replication. The mechanism by which 3-HCL-C interfered with HCV replication was shown to include induction of IFN-stimulated response element transcription and IFN-dependent antiviral gene expression (Wu et al.2012).
Developments in the treatment of HCV genotype 3 infection
Published in Expert Review of Anti-infective Therapy, 2019
The combination of DCV with SOF administered once daily for 12 or 24 weeks was the first oral DAA-only regimen to demonstrate very promising efficacy (98% SVR) in non-cirrhotic patients infected with GT1 through GT3 [43]. Patients were either treatment-naïve or -experienced including prior failures to telaprevir or boceprevir. Of 18 treated GT3 patients, one GT3a patient was a virologic failure; this patient had a preexisting NS5A RAS, A30K that was also the only RAS detected at relapse. The impact of preexisting NS5A RASs on SVR was unclear in this trial since four other patients with preexisting NS5A RASs reported to confer higher resistance to DCV than A30K in vitro [44] achieved SVR. Three were GT3a patients with Y93H and one was a GT3b patient with A30K combined with L31M [45]. The safety and efficacy profiles of this DAA-only regimen provided the basis for its approval in 2014 [46].