title: Application of phosphoramidate ProTide technology significantly improves antiviral potency of carbocyclic adenosine derivatives.
abstract: We report the application of phosphoramidate pronucleotide (ProTide) technology to the antiviral agent carbocyclic L-d4A (L-Cd4A). The phenyl methyl alaninyl parent ProTide of L-Cd4A was prepared by Grignard-mediated phosphorochloridate reaction and resulted in a compound with significantly improved anti-HIV (2600-fold) and HBV activity. We describe modifications of the aryl, ester, and amino acid regions of the ProTide and how these changes affect antiviral activity and metabolic stability. Separate and distinct SARs were noted for HIV and HBV. Additionally, ProTides were prepared from the D-nucleoside D-Cd4A and the dideoxy analogues L-CddA and D-CddA. These compounds showed more modest potency improvements over the parent drug. In conclusion, the ProTide approach is highly successful when applied to L-Cd4A with potency improvements in vitro as high as 9000-fold against HIV. With a view to preclinical candidate selection we carried out metabolic stability studies using cynomolgus monkey liver and intestinal S9 fractions.
authors.affiliation: Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3XF, UK. mcguigan@cardiff.ac.uk
authors.forename: Christopher
authors.initials: C
authors.lastname: McGuigan
authors.forename: Alshaimaa
authors.initials: A
authors.lastname: Hassan-Abdallah
authors.forename: Sheila
authors.initials: S
authors.lastname: Srinivasan
authors.forename: Yikang
authors.initials: Y
authors.lastname: Wang
authors.forename: Adam
authors.initials: A
authors.lastname: Siddiqui
authors.forename: Susan M
authors.initials: SM
authors.lastname: Daluge
authors.forename: Kristjan S
authors.initials: KS
authors.lastname: Gudmundsson
authors.forename: Huiqiang
authors.initials: H
authors.lastname: Zhou
authors.forename: Ed W
authors.initials: EW
authors.lastname: McLean
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Peckham
authors.forename: Thimysta C
authors.initials: TC
authors.lastname: Burnette
authors.forename: Harry
authors.initials: H
authors.lastname: Marr
authors.forename: Richard
authors.initials: R
authors.lastname: Hazen
authors.forename: Lynn D
authors.initials: LD
authors.lastname: Condreay
authors.forename: Lance
authors.initials: L
authors.lastname: Johnson
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D006515:Hepatitis B virus / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D009711:Nucleotides / Q000138:chemical synthesis / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D000998:Antiviral Agents; D009711:Nucleotides; D009943:Organophosphorus Compounds; D000241:Adenosine