Prodrug technology

In a simplified manner, prodrugs are masked forms of active drugs that are designed to be activated once they have administered into the body. Prodrugs are considered to be inactive or at least significantly less active than the released real drugs and therefore they have to undergo an enzymatic or chemical biotransformation before eliciting their pharmacological effects. The rationale behind the use of prodrugs is generally to optimize physicochemical, pharmaceutical and pharmacokinetic properties (such as aqueous solubility, permeability, bioavailability, chemical stability and duration of action), which can lead, if unfavourable, to considerable problems in later drug development. Additionally, the prodrug strategy has been used to increase the selectivity of drugs for their intended target. This improves not only the efficacy of the drug, but also decreases systemic and/or unwanted tissue/organ-specific toxicity. Development of a prodrug with improved properties may also represent a life-cycle management opportunity. In recent years, numerous prodrugs, designed to overcome formulation, delivery, and toxicity barriers to drug utilization, have reached the market. Approximately 10% of all marketed small molecular drugs are prodrugs.

 

In our research group, we are actively developing novel prodrug methods to improve usefulness of investigational drugs, as well as drugs already on the market or withdrawn from the market.

More detailed research topics are

1. Prodrugs enhancing the aqueous solubility of a drug molecule

- incorporation of ionizable or polar groups

2. Prodrugs enhancing the absorption of a drug molecule

- increasing the lipophilicity
- targeting amino acid and/or peptide transporters

3. Prodrugs targeting large neutral amino acid transporter 1 (LAT1)

- central nervous system (CNS delivery)
- tumors

4. Prodrugs targeting cytochrome P450- enzymes

- hepatocytes

 

Methods

Molecular modeling is used in our target- and ligand-based (pro)drug design. The search of novel promoieties is made from available molecular databases and based on information derived from the target protein and known active compounds.

Novel prodrugs are designed to overcome the prevailing barrier(s) or to be activated site-selectively by using different promoieties attached to the functional group(s) of the parent drug either directly or via various linkers or spacers. The designed prodrug molecules are synthesized, purified, and characterized in our state-of-the-art synthesis laboratories.

Physicochemical properties (e.g. distribution coefficient (log D), aqueous solubility) and chemical stabilities at various pH values as well as plasma protein binding of the novel prodrugs are determined in our state-of-the-art analysis laboratories. The rate and quantity of the released parent drugs are evaluated in vitro in various enzyme-containing media and buffered solutions containing pure enzymes.

L-Type amino acid transporter (LAT1)- mediated uptake of prodrugs into the cells are evaluated in MCF-7 cell line and targeting efficacy with more sophisticated in vivo studies.

RESEARCH TEAM

Contact person / Group Leader
Professor Jarkko Rautio (pharmaceutical chemistry)
(jarkko.rautio [at] uef.fi)

Prodrug Design, Synthesis and in Vitro Characterization
Ph.D. Kristiina Huttunen (medicinal chemistry)

In Vivo Evaluation and Bioanalytics
Ph.D. Mikko Gynther (pharmaceutical chemistry)

Other Group Members
Ph.D. Jukka Leppänen, adj. prof. (docent) (organic chemistry), Senior Lecturer
Ph.D. Krista Laine (pharmaceutical chemistry), Lecturer

Doctoral Students
M.Sc. Kalle Malmioja (organic chemistry)
B.Sc. Jussi Kärkkäinen (pharmaceutical chemistry)

Technicians
Mrs Helly Rissanen
Mrs Tiina Koivunen

SELECTED PUBLICATIONS

  1. Design, Synthesis and Brain Uptake of LAT1-Targeted Amino Acid Prodrugs of Dopamine. Peura et. al. Pharm30(10): 2523-2537, 2013http://dx.doi.org/10.1007/s11095-012-0966-3


  2. Brain uptake of ketoprofein-lysine prodrug in rats. Gynther et. al. Int. J. Pharm. 399(1-2): 121-128, 2010http://dx.doi.org/10.1016/j.ijpharm.2010.08.019


  3. Prodrugs from serendipity to rational design. Huttunen et. al. Pharmacol. Rev. 63(3): 750-771, 2011http://dx.doi.org/10.1124/pr.110.003459


  4. Prodrugs - design and pharmaceutical applications. Rautio et. al. Nat. Rev. Drug Discov. 7(3): 255-270, 2008http://dx.doi.org/10.1038/nrd2468