title: Phosphorodiamidates as a promising new phosphate prodrug motif for antiviral drug discovery: application to anti-HCV agents.
abstract: We herein report phosphorodiamidates as a significant new phosphate prodrug motif. Sixty-seven phosphorodiamidates are reported of two 6-O-alkyl 2'-C-methyl guanosines, with significant variation in the diamidate structure. Both symmetrical and asymmetric phosphorodiamidates are reported, derived from various esterified amino acids, both d and l, and also from various simple amines. All of the compounds were evaluated versus hepatitis C virus in replicon assay, and nanomolar activity levels were observed. Many compounds were noncytotoxic at 100 μM, leading to high antiviral selectivities. The agents are stable in acidic, neutral, and moderately basic media and in selected biological media but show efficient processing by carboxypeptidases and efficiently yield the free nucleoside monophosphate in cells. On the basis of in vitro data, eight leads were selected for additional in vivo evaluation, with the intent of selecting one candidate for progression toward clinical studies. This phosphorodiamidate prodrug method may have broad application outside of HCV and antivirals as it offers many of the advantages of phosphoramidate ProTides but without the chirality issues present in most cases.
authors: Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK. mcguigan@cardiff.ac.uk
authors: Christopher
authors: C
authors: McGuigan
authors: Karolina
authors: K
authors: Madela
authors: Mohamed
authors: M
authors: Aljarah
authors: Claire
authors: C
authors: Bourdin
authors: Maria
authors: M
authors: Arrica
authors: Emma
authors: E
authors: Barrett
authors: Sarah
authors: S
authors: Jones
authors: Alexander
authors: A
authors: Kolykhalov
authors: Blair
authors: B
authors: Bleiman
authors: K Dawn
authors: KD
authors: Bryant
authors: Babita
authors: B
authors: Ganguly
authors: Elena
authors: E
authors: Gorovits
authors: Geoffrey
authors: G
authors: Henson
authors: Damound
authors: D
authors: Hunley
authors: Jeff
authors: J
authors: Hutchins
authors: Jerry
authors: J
authors: Muhammad
authors: Aleksandr
authors: A
authors: Obikhod
authors: Joseph
authors: J
authors: Patti
authors: C Robin
authors: CR
authors: Walters
authors: Jin
authors: J
authors: Wang
authors: John
authors: J
authors: Vernachio
authors: Changalvala V S
authors: CV
authors: Ramamurty
authors: Srinivas K
authors: SK
authors: Battina
authors: Stanley
authors: S
authors: Chamberlain
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D043402:Cathepsin A / Q000378:metabolism; D002460:Cell Line; D004355:Drug Stability; D006151:Guanosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044967:Serum; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D009943:Organophosphorus Compounds; D011355:Prodrugs; D006151:Guanosine; D043402:Cathepsin A