title: Synthesis and pre-clinical studies of new amino-acid ester thiazolide prodrugs.
abstract: Thiazolides are polypharmacology agents with at least three mechanisms of action against a broad spectrum of parasites, bacteria and viruses. In respiratory viruses they inhibit the replication of orthomyxoviridae and paramyxoviridae at a post-translational level. Nitazoxanide 1a, the prototype thiazolide, was originally developed as an antiparasitic agent and later repurposed for the treatment of viral respiratory infections. The second generation thiazolides following nitazoxanide, such as the 5-chloro analogue RM-5038 2a, are also broad-spectrum antiviral agents as we have reported. Both 1a and its effective circulating metabolite, tizoxanide 1b, are 5-nitrothiazole derivatives, while RM-5038 2a and its de-acetyl derivative RM-4848 2b are the corresponding 5-chloro derivatives. Recently 1a has completed phase II-III clinical trials in the United States, Canada, Australia and New Zealand in a total of 2865 adults and adolescents of at least 12 months of age with viral acute respiratory illness. Since its biodisposition is primarily seen in the gastro-intestinal tract, its efficacy in systemic viral diseases requires relatively high oral doses. The chemical synthesis of new derivatives with a better systemic absorption was therefore urgently needed. In order to improve their systemic absorption, new amino-ester prodrug derivatives of 1b and RM4848 2b were prepared and tested for their animal pharmacology, pharmacokinetics and toxicology. RM-5061 8a in rats showed 7-fold higher blood concentration compared to 1a: absolute bioavailability increased from 3 to 20%, with a good safety profile in animal safety pharmacology and toxicology.
authors.affiliation: Robert Robinson Laboratories, Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK. Electronic address: stachuls@liv.ac.uk.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Stachulski
authors.affiliation: Bio-Techne, The Watkins Building, Atlantic Road, Bristol BS11 9QD, UK.
authors.forename: Karl
authors.initials: K
authors.lastname: Swift
authors.affiliation: Bio-Techne, The Watkins Building, Atlantic Road, Bristol BS11 9QD, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Cooper
authors.affiliation: Bio-Techne, The Watkins Building, Atlantic Road, Bristol BS11 9QD, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Reynolds
authors.affiliation: Calvert Laboratories, Inc., Scott Township, PA 18447, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Norton
authors.affiliation: Calvert Laboratories, Inc., Scott Township, PA 18447, United States.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Slonecker
authors.affiliation: Romark Laboratories, L.C., Tampa, 33609 FL, United States.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Rossignol
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D001682:Biological Availability; D060326:Chemistry Techniques, Synthetic; D004353:Drug Evaluation, Preclinical; D004952:Esters / Q000737:chemistry*; D005260:Female; D008297:Male; D009975:Orthomyxoviridae / Q000187:drug effects / Q000502:physiology; D010252:Paramyxoviridae / Q000187:drug effects / Q000502:physiology; D011355:Prodrugs / Q000378:metabolism*; D051381:Rats; D012449:Safety; D013844:Thiazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000596:Amino Acids; D000998:Antiviral Agents; D004952:Esters; D011355:Prodrugs; D013844:Thiazoles
keywords: Antiviral agents; Biodisposition; Chemical synthesis; Oral absorption; Pharmacology; Prodrugs; Stability; Toxicology