3825331
Analytical methods development for the measurement of physico-chemical parameters of a new antiviral in pre-clinical stage | Poster Board #715
Date
March 29, 2023
Acyclonucleoside phosphonates (ANP) pro-drugs have shown to be active against various DNA, RNA and retroviruses. These ANP derivatives improved cell penetration and decreased nephrotoxicity. Today, several active drugs against HBV are commercially available, such as Hepsera© (bis(POM)PMEA or Adefovir®dipivoxil) and Viread© (bis(POC)PMPA or Tenofovir® disoproxil).
However, different side effects are common and the activity of these drugs can be improved.
For this reason, our group has developed a new family of ANPs based on a trans-but-2-enyl phosphonate moiety. Among the many compounds synthesized, LAVR-289, a triple prodrug, has shown remarkable antiviral properties at nM concentrations on several DNA viruses including POX viruses. Additionally, LAVR-289 has not shown toxicity in mice.
At the pre-clinical development stage the physico-chemical parameters such as pKa value, logP, and critical micellar concentration (self-organisation), of LAVR-289 have been determined by UV spectroscopy, HPLC-UV method, and fluorescence spectroscopy, respectively.
A liquid chromatography method has been developed to separate isomers Z and E of LAVR-289, because only the Z form is bioactive. This methodology was used in semi-preparative chromatography to purify active molecule in laboratory scale. In the same manner, due to the presence of a chiral phosphorous, the challenging chiral separation of four diastereo-isomers was achieved.
We have monitored the chemical and plasma stabilities by HPLC-UV, which allowed us to determine some metabolites (characterized by NMR and HRMS) and find the human plasma half-time stability of around 6 hours. This duration is longer than the bis(POC)LAVR analogue.
These preliminary data are of great interest for the pre-clinical and clinical development of this novel broad-spectrum antiviral.
However, different side effects are common and the activity of these drugs can be improved.
For this reason, our group has developed a new family of ANPs based on a trans-but-2-enyl phosphonate moiety. Among the many compounds synthesized, LAVR-289, a triple prodrug, has shown remarkable antiviral properties at nM concentrations on several DNA viruses including POX viruses. Additionally, LAVR-289 has not shown toxicity in mice.
At the pre-clinical development stage the physico-chemical parameters such as pKa value, logP, and critical micellar concentration (self-organisation), of LAVR-289 have been determined by UV spectroscopy, HPLC-UV method, and fluorescence spectroscopy, respectively.
A liquid chromatography method has been developed to separate isomers Z and E of LAVR-289, because only the Z form is bioactive. This methodology was used in semi-preparative chromatography to purify active molecule in laboratory scale. In the same manner, due to the presence of a chiral phosphorous, the challenging chiral separation of four diastereo-isomers was achieved.
We have monitored the chemical and plasma stabilities by HPLC-UV, which allowed us to determine some metabolites (characterized by NMR and HRMS) and find the human plasma half-time stability of around 6 hours. This duration is longer than the bis(POC)LAVR analogue.
These preliminary data are of great interest for the pre-clinical and clinical development of this novel broad-spectrum antiviral.
Structures of Adefovir® dipivoxil, Tenofovir® disoproxil and LAVR-289
Presenter
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